11-2445106-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000218.3(KCNQ1):c.8C>G(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 942,112 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 3 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=0.30290502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.8C>G	p.Ala3Gly	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.8C>G	p.Ala3Gly	missense_variant	1/15
KCNQ1	NM_001406838.1	c.8C>G	p.Ala3Gly	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-355C>G		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.8C>G	p.Ala3Gly	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.8C>G	p.Ala3Gly	missense_variant	1/11
KCNQ1	ENST00000496887.7	c.24-277C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 942112 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 443926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000238

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostArm	Benign	0.0012
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.020	D
Sift4G	Benign	0.24	T
Polyphen		0.038	B
Vest4		0.25
MutPred		0.20		Gain of catalytic residue at A3 (P = 0.0084);
MVP		0.91
MPC		1.2
ClinPred		0.31	T
GERP RS		2.7
Varity_R		0.051
gMVP		0.29

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: rs794728543; hg19: chr11-2466336;