rs1060500622

chr11-2445136-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000218.3(KCNQ1):c.38A>G(p.Lys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,112,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.302

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Disordered (size 27) in uniprot entity KCNQ1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18322188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.38A>G	p.Lys13Arg	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.38A>G	p.Lys13Arg	missense_variant	1/15
KCNQ1	NM_001406838.1	c.38A>G	p.Lys13Arg	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-325A>G		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.38A>G	p.Lys13Arg	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.38A>G	p.Lys13Arg	missense_variant	1/11
KCNQ1	ENST00000496887.7	c.24-247A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147468 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 2 AN: 965062 Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 2 AN XY: 458864

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: 0.00000237

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147468 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71798

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000302

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 12, 2021

This sequence change replaces lysine with arginine at codon 13 of the KCNQ1 protein (p.Lys13Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 405256). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
CardioboostArm	Uncertain	0.12
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.27
Sift	Benign	0.19	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.092
MutPred		0.089		Loss of methylation at K13 (P = 0.0128);
MVP		0.90
MPC		1.1
ClinPred		0.081	T
GERP RS		1.5
Varity_R		0.043
gMVP		0.18

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: rs1060500622; hg19: chr11-2466366;