11-2847899-G-A

Variant names:

• chr11-2847899-G-A
• rs1800172
• NM_000218.3:c.1927G>A
• KCNQ1 p.Gly643Ser

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP6_Very_Strong

The NM_000218.3(KCNQ1):c.1927G>A (p.Gly643Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00295 (AC=4,657) in the gnomAD database across 1,580,300 control chromosomes, including 73 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0466. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G643D: Uncertain_significance (ClinVar VariationId 923434, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (56 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: -4.71
• Publications: 31 publications found

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• long QT syndrome 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1-AS1 (HGNC:42790): ()

Classification according to ACMG Germline Pathogenicity v2019

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (20/20 total B/LB).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0466 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 73.; Very high cumulative gnomAD AC = 4657 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 NM_000218.3	MANE Select	c.1927G>A p.Gly643Ser	missense	Exon 16 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.1831G>A p.Gly611Ser	missense	Exon 15 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.1657G>A p.Gly553Ser	missense	Exon 17 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.1927G>Ap.Gly643Ser

Exon rankExon 16 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.1831G>Ap.Gly611Ser

Exon rankExon 15 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.1657G>Ap.Gly553Ser

Exon rankExon 17 of 17

missense

Prot: NP_001393766.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 ENST00000155840.12	TSL:1MANE Select	c.1927G>A p.Gly643Ser	missense	Exon 16 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.1546G>A p.Gly516Ser	missense	Exon 16 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.1924G>A p.Gly642Ser	missense	Exon 16 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.1927G>Ap.Gly643Ser

Exon rankExon 16 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.1546G>Ap.Gly516Ser

Exon rankExon 16 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.1924G>Ap.Gly642Ser

Exon rankExon 16 of 16

missense

Prot: ENSP00000581056.1UniProt: A0ACI8SIJ2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00789	AC:1201	Hom:16	AN:152152	Cov:33
GnomAD2 exomes	AF: 0.00616	AC:1198	Hom:	AN:194370	Cov:
GnomAD4 exome	AF: 0.00242	AC:3451	Hom:56	AN:1428030	Cov:31
GnomAD4 genome	AF: 0.00792	AC:1206	Hom:17	AN:152270	Cov:33
TOPMed (Bravo)	AF: 0.00875	AC:2317	Hom:35	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00413	AC:1035	Hom:8	AN:250862	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00726	AC:17	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00689	AC:88	Hom:	AN:12770	Cov:
GenomeAsia100K	AF: 0.0110	AC:39	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0530	AC:385	Hom:	AN:7224	Cov:
Qatari Genome	AF: 0.00320	AC:6	Hom:	AN:1880	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0514	AC:6268	Hom:175	AN:121914	Cov:
Turkish Variome	AF: 0.000490	AC:3	Hom:0	AN:6120	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0376	AC:337	Hom:11	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.00527	221	41958	0.00320	214	66886
SCHEMA(Schizophrenia)	0.0177	1960	110958	0.0130	2389	184334

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (5)
-	-	3	Long QT syndrome 1 (3)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Short QT syndrome type 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.17
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.016
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0044	N
FuncVEP CTI	Benign	0.0023
GPN-Star LLR	N/A	-0.87
GPN-Star score	N/A	0.87
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0035	T
MetaSVM	Uncertain	0.24	D
Mutation Taster	N/A	77/23	polymorphism
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	-4.7
popEVE	Benign	-2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.76	N
REVEL	Uncertain	0.57
Sift	Benign	0.58	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.032
VESM-3B	Benign	-2.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1800172;

hg19: chr11-2869129;

COSMIC: COSV50110156;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar