11-2847638-G-A

Position:

• chr11-2847638-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.1795-129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.072 in 843,118 control chromosomes in the GnomAD database, including 3,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (491 hom., cov: 33)
  • Exomes 𝑓: 0.073 (2639 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0680

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-2847638-G-A is Benign according to our data. Variant chr11-2847638-G-A is described in ClinVar as [Benign]. Clinvar id is 1231618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1795-129G>A		intron_variant		ENST00000155840.12	NP_000209.2
KCNQ1-AS1	NR_130721.1	n.778-7196C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1795-129G>A		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7196C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9931 AN: 152146 Hom.: 491 Cov.: 33

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.0565

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0685

GnomAD4 exome AF: 0.0734 AC: 50724 AN: 690854 Hom.: 2639 AF XY: 0.0731 AC XY: 26424 AN XY: 361486

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.0514

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.0855

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0631

Gnomad4 OTH exome AF: 0.0652

GnomAD4 genome AF: 0.0653 AC: 9940 AN: 152264 Hom.: 491 Cov.: 33 AF XY: 0.0692 AC XY: 5148 AN XY: 74432

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.0564

Gnomad4 SAS AF: 0.0810

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0649

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0636 Hom.: 71

Bravo AF: 0.0664

Asia WGS AF: 0.0640 AC: 222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.92
DANN	Benign	0.87

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: rs79788804; hg19: chr11-2868868; COSMIC: COSV50140486;