chr11-2532919-A-G

Variant names:

• chr11-2532919-A-G
• rs179436
• NM_000218.3:c.477+4901A>G

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 -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_000218.3(KCNQ1):c.477+4901A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.803 (AC=122,183) in the gnomAD database across 152,096 control chromosomes, including 49,407 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.952. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: 𝑓 0.80 (49407 hom., cov: 33)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30
• Publications: 6 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

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 -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9523 — exceeds 5%% threshold (BA1 applied)

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.477+4901A>G		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.477+4901A>G		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.207+4901A>G		intron	N/A	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.477+4901A>G		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.96+4901A>G		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.477+4901A>G		intron	N/A	ENSP00000581056.1	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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.803	AC:122078	Hom:49357	AN:151978	Cov:33
GnomAD4 genome	AF: 0.803	AC:122183	Hom:49407	AN:152096	Cov:33
TOPMed (Bravo)	AF: 0.801	AC:212019	Hom:85703	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.816	AC:171095	Hom:70019	AN:209640	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.811	AC:1900	Hom:783	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.975	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.830	AC:249	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.903	AC:3138	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.992	AC:7174	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.750	AC:132	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.993	AC:121815	Hom:60485	AN:122669	Cov:
Turkish Variome	AF: 0.780	AC:1206	Hom:477	AN:1546	Cov:
UK10K	AF: 0.837	AC:6326	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.969	AC:8685	Hom:4213	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.17
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.67
GPN-Star LLR	N/A	0.47
GPN-Star score	N/A	-0.47
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.3

Showing 8 of 8 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.

Other links and lift over

dbSNP: rs179436;

hg19: chr11-2554149;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar