11-2847648-T-C

Variant names:

• chr11-2847648-T-C
• rs3852520
• NM_000218.3:c.1795-119T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.1795-119T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 911,196 control chromosomes in the GnomAD database, including 76,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13468 hom., cov: 33)
  • Exomes 𝑓: 0.39 (62677 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2847648-T-C is Benign according to our data. Variant chr11-2847648-T-C is described in ClinVar as [Benign]. Clinvar id is 671899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1795-119T>C		intron_variant	Intron 15 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1795-119T>C		intron_variant	Intron 15 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61732 AN: 151982 Hom.: 13457 Cov.: 33

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.430

GnomAD4 exome AF: 0.387 AC: 293522 AN: 759096 Hom.: 62677 AF XY: 0.388 AC XY: 153123 AN XY: 394738

African (AFR) AF: 0.444 AC: 8708 AN: 19622

American (AMR) AF: 0.553 AC: 18598 AN: 33640

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 7695 AN: 20164

East Asian (EAS) AF: 0.866 AC: 28469 AN: 32882

South Asian (SAS) AF: 0.478 AC: 30621 AN: 64126

European-Finnish (FIN) AF: 0.369 AC: 13625 AN: 36892

Middle Eastern (MID) AF: 0.402 AC: 1355 AN: 3374

European-Non Finnish (NFE) AF: 0.332 AC: 169491 AN: 511216

Other (OTH) AF: 0.402 AC: 14960 AN: 37180

GnomAD4 genome AF: 0.406 AC: 61788 AN: 152100 Hom.: 13468 Cov.: 33 AF XY: 0.413 AC XY: 30708 AN XY: 74354

African (AFR) AF: 0.438 AC: 18162 AN: 41496

American (AMR) AF: 0.498 AC: 7611 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3470

East Asian (EAS) AF: 0.860 AC: 4437 AN: 5162

South Asian (SAS) AF: 0.492 AC: 2375 AN: 4826

European-Finnish (FIN) AF: 0.379 AC: 4014 AN: 10586

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22478 AN: 67954

Other (OTH) AF: 0.431 AC: 906 AN: 2104

Alfa AF: 0.363 Hom.: 1260

Bravo AF: 0.418

Asia WGS AF: 0.635 AC: 2205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3852520; hg19: chr11-2868878; COSMIC: COSV50137921;