rs2075870

Positions:

• chr11-2768789-G-A
• chr11-2768789-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000218.3(KCNQ1):​c.1515-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,373,006 control chromosomes in the GnomAD database, including 2,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.055 (401 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1861 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.461

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-2768789-G-A is Benign according to our data. Variant chr11-2768789-G-A is described in ClinVar as [Benign]. Clinvar id is 1234116.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2768789-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1515-55G>A		intron_variant		ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1515-55G>A		intron_variant		1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.1134-55G>A		intron_variant		1
KCNQ1	ENST00000496887.7	c.1158-55G>A		intron_variant		5
KCNQ1	ENST00000646564.2	c.975-55G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8279 AN: 152096 Hom.: 398 Cov.: 32

Gnomad AFR AF: 0.0992

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.0888

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0603

GnomAD4 exome AF: 0.0365 AC: 44597 AN: 1220792 Hom.: 1861 AF XY: 0.0379 AC XY: 23484 AN XY: 619172

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.0958

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.0817

Gnomad4 FIN exome AF: 0.00641

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0486

GnomAD4 genome AF: 0.0545 AC: 8298 AN: 152214 Hom.: 401 Cov.: 32 AF XY: 0.0546 AC XY: 4062 AN XY: 74420

Gnomad4 AFR AF: 0.0995

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0917

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.0882

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0350 Hom.: 48

Bravo AF: 0.0594

Asia WGS AF: 0.115 AC: 401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.79
DANN	Benign	0.76

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: rs2075870; hg19: chr11-2790019; COSMIC: COSV50105827; COSMIC: COSV50105827;