NM_000218.3:c.1942G>A

Variant names:

• chr11-2847914-G-A
• rs34150427
• NM_000218.3:c.1942G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000218.3(KCNQ1):​c.1942G>A​(p.Val648Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,576,322 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V648F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (10 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -0.554
• Publications: 11 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 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=0.0043562353).
• BP6: Variant 11-2847914-G-A is Benign according to our data. Variant chr11-2847914-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00673 (1025/152246) while in subpopulation AFR AF = 0.0233 (969/41548). AF 95% confidence interval is 0.0221. There are 6 homozygotes in GnomAd4. There are 477 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.1942G>A	p.Val648Ile	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1846G>A	p.Val616Ile	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1672G>A	p.Val558Ile	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1942G>A	p.Val648Ile	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1561G>A	p.Val521Ile	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1939G>A	p.Val647Ile	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152128 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00145 AC: 269 AN: 185112 AF XY: 0.00122

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000691

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000652

Gnomad OTH exome AF: 0.000414

GnomAD4 exome AF: 0.000667 AC: 950 AN: 1424076 Hom.: 10 Cov.: 31 AF XY: 0.000579 AC XY: 408 AN XY: 704970

African (AFR) AF: 0.0235 AC: 766 AN: 32600

American (AMR) AF: 0.000893 AC: 36 AN: 40330

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37448

South Asian (SAS) AF: 0.000122 AC: 10 AN: 81640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49070

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5704

European-Non Finnish (NFE) AF: 0.0000366 AC: 40 AN: 1093002

Other (OTH) AF: 0.00156 AC: 92 AN: 58872

GnomAD4 genome AF: 0.00673 AC: 1025 AN: 152246 Hom.: 6 Cov.: 33 AF XY: 0.00641 AC XY: 477 AN XY: 74454

African (AFR) AF: 0.0233 AC: 969 AN: 41548

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00756

ESP6500AA AF: 0.0177 AC: 76

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.00147 AC: 175

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.083
DANN	Benign	0.80
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.55
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.89	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.030
MVP		0.76
MPC		0.30
ClinPred		0.0050	T
GERP RS		-1.3
Varity_R		0.020
gMVP		0.36
Mutation Taster		=92/8	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: rs34150427; hg19: chr11-2869144; COSMIC: COSV105843729;