rs199473442

Variant names:

• chr11-2445103-C-G
• rs199473442
• NM_000218.3:c.5C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-2445103-C-G
• chr11-2445103-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.301
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP5: Variant 11-2445103-C-G is Pathogenic according to our data. Variant chr11-2445103-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431053.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-358C>G		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 940006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 442668

African (AFR) AF: 0.00 AC: 0 AN: 17956

American (AMR) AF: 0.00 AC: 0 AN: 4150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8392

East Asian (EAS) AF: 0.00 AC: 0 AN: 13234

South Asian (SAS) AF: 0.00 AC: 0 AN: 20280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2112

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828850

Other (OTH) AF: 0.00 AC: 0 AN: 33302

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Jul 27, 2017

Biotechnology Research Center, Pasteur Institute of Iran

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

According to the ACMG standards and guidelines, the following evidences results in the likely pathogenic variant: Not reported in ExAC and 1000G project and in more than 1000 unrelated Iranian individuals (PM2) but known disease mutation at this position (HGMD ID: CM097076, ClinVar ID: 67091) (PM5) Co segregated with the disease in the family (PP1) Missense variants in KCNQ1 gene are a common mechanism of the LQT1 disease (PP2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
CardioboostArm	Benign	0.00044
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.30
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.36
Sift	Benign	0.65	T
Sift4G	Benign	0.53	T
Polyphen		0.032	B
Vest4		0.35
MutPred		0.24		Gain of MoRF binding (P = 0.1134);
MVP		0.90
MPC		1.2
ClinPred		0.37	T
GERP RS		1.7
PromoterAI		0.26	Neutral
Varity_R		0.034
gMVP		0.28
Mutation Taster		=57/43	disease causing (ClinVar)

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: rs199473442; hg19: chr11-2466333;