11-2848414-C-T

Position:

• chr11-2848414-C-T

Variant summary

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

The ENST00000155840.12(KCNQ1):​c.*411C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 477,920 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (118 hom., cov: 33)
  • Exomes 𝑓: 0.023 (120 hom.)
• Consequence: KCNQ1 ENST00000155840.12 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.667

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=-0.72).
• BP6: Variant 11-2848414-C-T is Benign according to our data. Variant chr11-2848414-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 304247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.*411C>T		3_prime_UTR_variant	16/16	ENST00000155840.12	NP_000209.2
KCNQ1-AS1	NR_130721.1	n.778-7972G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.*411C>T		3_prime_UTR_variant	16/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.*411C>T		3_prime_UTR_variant	16/16	1		ENSP00000334497
KCNQ1-AS1	ENST00000440887.2	n.777-7972G>A		intron_variant, non_coding_transcript_variant		5
KCNQ1	ENST00000496887.7	c.*411C>T		3_prime_UTR_variant	16/16	5		ENSP00000434560

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5146 AN: 152156 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0230 AC: 2996 AN: 130102 Hom.: 59 AF XY: 0.0218 AC XY: 1547 AN XY: 70818

Gnomad AFR exome AF: 0.0621

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00643

Gnomad FIN exome AF: 0.00696

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0227 AC: 7406 AN: 325646 Hom.: 120 Cov.: 0 AF XY: 0.0212 AC XY: 3884 AN XY: 183556

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00620

Gnomad4 FIN exome AF: 0.00703

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0338 AC: 5145 AN: 152274 Hom.: 118 Cov.: 33 AF XY: 0.0318 AC XY: 2371 AN XY: 74456

Gnomad4 AFR AF: 0.0599

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0323 Hom.: 23

Bravo AF: 0.0369

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Long QT syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atrial fibrillation, familial, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Short QT syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.6
DANN	Benign	0.90

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: rs45460605; hg19: chr11-2869644;