11-2445119-G-C

Variant names:

• chr11-2445119-G-C
• rs773966802
• NM_000218.3:c.21G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000218.3(KCNQ1):​c.21G>C​(p.Pro7Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000676 in 147,972 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.722
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-2445119-G-C is Benign according to our data. Variant chr11-2445119-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2178080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.722 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.21G>C	p.Pro7Pro	synonymous	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 957068 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 453260

African (AFR) AF: 0.00 AC: 0 AN: 18254

American (AMR) AF: 0.00 AC: 0 AN: 4730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8936

East Asian (EAS) AF: 0.00 AC: 0 AN: 14248

South Asian (SAS) AF: 0.00 AC: 0 AN: 22390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839414

Other (OTH) AF: 0.00 AC: 0 AN: 34104

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 147972 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72058

African (AFR) AF: 0.00 AC: 0 AN: 41062

American (AMR) AF: 0.00 AC: 0 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66264

Other (OTH) AF: 0.00 AC: 0 AN: 2044

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		-0.72
PromoterAI		-0.10	Neutral

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: rs773966802; hg19: chr11-2466349;