11-2848878-A-G

Position:

• chr11-2848878-A-G

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.*875A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 453,932 control chromosomes in the GnomAD database, including 38,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12571 hom., cov: 34)
  • Exomes 𝑓: 0.39 (26039 hom.)
• Consequence: KCNQ1 NM_000218.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.637

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 11-2848878-A-G is Benign according to our data. Variant chr11-2848878-A-G is described in ClinVar as [Benign]. Clinvar id is 304262.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/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.*875A>G		3_prime_UTR_variant	16/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.*875A>G		3_prime_UTR_variant	16/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.*875A>G		3_prime_UTR_variant	16/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.*875A>G		3_prime_UTR_variant	16/16	5		ENSP00000434560.2
KCNQ1-AS1	ENST00000440887.2	n.777-8436T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59445 AN: 152012 Hom.: 12562 Cov.: 34

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.446 AC: 58181 AN: 130514 Hom.: 14737 AF XY: 0.441 AC XY: 31401 AN XY: 71234

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.872

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.395 AC: 119100 AN: 301802 Hom.: 26039 Cov.: 0 AF XY: 0.400 AC XY: 68770 AN XY: 171994

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.552

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.391 AC: 59495 AN: 152130 Hom.: 12571 Cov.: 34 AF XY: 0.399 AC XY: 29669 AN XY: 74360

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.859

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.409

Alfa AF: 0.342 Hom.: 9941

Bravo AF: 0.402

Asia WGS AF: 0.627 AC: 2176 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 22199116, 27531917) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Atrial fibrillation, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Short QT syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Congenital long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.068
DANN	Benign	0.41

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: rs8234; hg19: chr11-2870108;