11-2445279-C-T

Variant names:

• chr11-2445279-C-T
• rs1273257287
• NM_000218.3:c.181C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000218.3(KCNQ1):​c.181C>T​(p.Pro61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000052 in 1,153,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.765
• Publications: 0 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
• long QT syndrome 1

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2343564).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.181C>T	p.Pro61Ser	missense	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.181C>T	p.Pro61Ser	missense	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.181C>T	p.Pro61Ser	missense	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.181C>T	p.Pro61Ser	missense	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.181C>T	p.Pro61Ser	missense	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.181C>T	p.Pro61Ser	missense	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000520 AC: 6 AN: 1153328 Hom.: 0 Cov.: 31 AF XY: 0.00000536 AC XY: 3 AN XY: 559752

African (AFR) AF: 0.00 AC: 0 AN: 23172

American (AMR) AF: 0.00 AC: 0 AN: 10382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15052

East Asian (EAS) AF: 0.00 AC: 0 AN: 25846

South Asian (SAS) AF: 0.00 AC: 0 AN: 40414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3224

European-Non Finnish (NFE) AF: 0.00000622 AC: 6 AN: 964554

Other (OTH) AF: 0.00 AC: 0 AN: 46192

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
CardioboostArm	Benign	0.0015
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	8.7
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.46	N
PhyloP100		0.77
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.77	T
Polyphen		0.039	B
Vest4		0.11
MutPred		0.22		Gain of phosphorylation at P61 (P = 0.0077)
MVP		0.90
MPC		1.2
ClinPred		0.11	T
GERP RS		1.9
PromoterAI		-0.024	Neutral
Varity_R		0.033
gMVP		0.29
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1273257287; hg19: chr11-2466509;