rs12577654

Positions:

• chr11-2662099-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000218.3(KCNQ1):​c.1514+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,614,068 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (168 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.791

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]

KCNQ1OT1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-2662099-C-T is Benign according to our data. Variant chr11-2662099-C-T is described in ClinVar as [Benign]. Clinvar id is 36435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2662099-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00611 (931/152300) while in subpopulation SAS AF= 0.046 (222/4828). AF 95% confidence interval is 0.041. There are 11 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+18C>T		intron_variant		ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+18C>T		intron_variant		1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 933 AN: 152182 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00954 AC: 2396 AN: 251170 Hom.: 58 AF XY: 0.0114 AC XY: 1542 AN XY: 135758

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0391

Gnomad SAS exome AF: 0.0449

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00439 AC: 6416 AN: 1461768 Hom.: 168 Cov.: 34 AF XY: 0.00554 AC XY: 4030 AN XY: 727182

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0391

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00611 AC: 931 AN: 152300 Hom.: 11 Cov.: 33 AF XY: 0.00685 AC XY: 510 AN XY: 74476

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00303 Hom.: 0

Bravo AF: 0.00541

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.59

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: rs12577654; hg19: chr11-2683329;