11-2445138-C-T

Position:

• chr11-2445138-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000218.3(KCNQ1):​c.40C>T​(p.Arg14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000718 in 975,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.989

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33536613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.40C>T	p.Arg14Cys	missense_variant	1/16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.40C>T	p.Arg14Cys	missense_variant	1/15		NP_001393765.1
KCNQ1	NM_001406838.1	c.40C>T	p.Arg14Cys	missense_variant	1/11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-323C>T		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.40C>T	p.Arg14Cys	missense_variant	1/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000646564.2	c.40C>T	p.Arg14Cys	missense_variant	1/11			ENSP00000495806.2
KCNQ1	ENST00000496887.7	c.24-245C>T		intron_variant		5		ENSP00000434560.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000718 AC: 7 AN: 975402 Hom.: 0 Cov.: 30 AF XY: 0.0000108 AC XY: 5 AN XY: 464570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000824

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported in the following publications (PMID:17276182). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.35
MutPred		0.33		Gain of catalytic residue at W15 (P = 8e-04);
MVP		0.96
MPC		2.4
ClinPred		0.91	D
GERP RS		1.7
Varity_R		0.17
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs199473444; hg19: chr11-2466368;