rs375845797

chr11-2570657-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000218.3(KCNQ1):c.507G>A(p.Thr169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.539

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-2570657-G-A is Benign according to our data. Variant chr11-2570657-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.539 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.507G>A	p.Thr169=	synonymous_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.507G>A	p.Thr169=	synonymous_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.126G>A	p.Thr42=	synonymous_variant	3/16	1
KCNQ1	ENST00000496887.7	c.246G>A	p.Thr82=	synonymous_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12778G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249594 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135376

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460376 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726588

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74482

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2016

p.Thr169Thr in exon 3 of KCNQ1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 2/11460 Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs375845797). -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.2
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375845797; hg19: chr11-2591887;