chr11-2847958-C-T

Variant names:

• chr11-2847958-C-T
• rs11601907
• NM_000218.3:c.1986C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000218.3(KCNQ1):​c.1986C>T​(p.Tyr662Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,564,370 control chromosomes in the GnomAD database, including 43,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2983 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40854 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: -2.57
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-2847958-C-T is Benign according to our data. Variant chr11-2847958-C-T is described in ClinVar as Benign. ClinVar VariationId is 42489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

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.1986C>T	p.Tyr662Tyr	synonymous	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1890C>T	p.Tyr630Tyr	synonymous	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1716C>T	p.Tyr572Tyr	synonymous	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.1986C>T	p.Tyr662Tyr	synonymous	Exon 16 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1605C>T	p.Tyr535Tyr	synonymous	Exon 16 of 16	ENSP00000334497.5
	KCNQ1	ENST00000910997.1		c.1983C>T	p.Tyr661Tyr	synonymous	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25916 AN: 152034 Hom.: 2984 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.172 AC: 30776 AN: 178672 AF XY: 0.174

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.0934

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.000505

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.229 AC: 323694 AN: 1412218 Hom.: 40854 Cov.: 34 AF XY: 0.227 AC XY: 157968 AN XY: 697170

African (AFR) AF: 0.0410 AC: 1330 AN: 32454

American (AMR) AF: 0.0994 AC: 3847 AN: 38688

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4431 AN: 25034

East Asian (EAS) AF: 0.000456 AC: 17 AN: 37296

South Asian (SAS) AF: 0.0965 AC: 7770 AN: 80482

European-Finnish (FIN) AF: 0.272 AC: 13288 AN: 48804

Middle Eastern (MID) AF: 0.160 AC: 912 AN: 5684

European-Non Finnish (NFE) AF: 0.259 AC: 280883 AN: 1085420

Other (OTH) AF: 0.192 AC: 11216 AN: 58356

GnomAD4 genome AF: 0.170 AC: 25909 AN: 152152 Hom.: 2983 Cov.: 33 AF XY: 0.168 AC XY: 12493 AN XY: 74378

African (AFR) AF: 0.0486 AC: 2021 AN: 41550

American (AMR) AF: 0.131 AC: 2012 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3468

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5166

South Asian (SAS) AF: 0.0852 AC: 411 AN: 4826

European-Finnish (FIN) AF: 0.258 AC: 2733 AN: 10584

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17456 AN: 67938

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.226 Hom.: 5738

Bravo AF: 0.154

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	2	not provided (3)
-	-	2	Long QT syndrome (2)
-	-	2	Long QT syndrome 1 (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.5
DANN	Benign	0.89
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs11601907; hg19: chr11-2869188; COSMIC: COSV50126746;