NM_000218.3:c.1515-55G>A

Variant names:

• chr11-2768789-G-A
• rs2075870
• NM_000218.3:c.1515-55G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.461
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1234116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1515-55G>A		intron_variant	Intron 11 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1515-55G>A		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

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

African (AFR) AF: 0.108 AC: 3114 AN: 28750

American (AMR) AF: 0.0220 AC: 975 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.0958 AC: 2361 AN: 24646

East Asian (EAS) AF: 0.209 AC: 8066 AN: 38588

South Asian (SAS) AF: 0.0817 AC: 6653 AN: 81430

European-Finnish (FIN) AF: 0.00641 AC: 341 AN: 53192

Middle Eastern (MID) AF: 0.0636 AC: 338 AN: 5312

European-Non Finnish (NFE) AF: 0.0226 AC: 20201 AN: 892118

Other (OTH) AF: 0.0486 AC: 2548 AN: 52412

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

African (AFR) AF: 0.0995 AC: 4133 AN: 41530

American (AMR) AF: 0.0322 AC: 492 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 318 AN: 3468

East Asian (EAS) AF: 0.208 AC: 1076 AN: 5162

South Asian (SAS) AF: 0.0882 AC: 425 AN: 4818

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1675 AN: 68000

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0353 Hom.: 55

Bravo AF: 0.0594

Asia WGS AF: 0.115 AC: 401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.79
DANN	Benign	0.76
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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