11-2847898-C-G

Variant names:

• chr11-2847898-C-G
• rs12720454
• NM_000218.3:c.1926C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000218.3(KCNQ1):​c.1926C>G​(p.Cys642Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C642F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.52
• Publications: 2 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20488328).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1926C>G	p.Cys642Trp	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1830C>G	p.Cys610Trp	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1656C>G	p.Cys552Trp	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1926C>G	p.Cys642Trp	missense	Exon 16 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1545C>G	p.Cys515Trp	missense	Exon 16 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.1785C>G	p.Cys595Trp	missense	Exon 15 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys642Trp variant in KCNQ1 has not been previously reported in individuals with Jervell and Lange-Nielsen syndrome. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction t ools and conservation analyses suggest that the p.Cys642Trp variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the clinical significance of the p.Cys642Trp variant is uncertain.

Cardiovascular phenotype Uncertain:1

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C642W variant (also known as c.1926C>G), located in coding exon 16 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 1926. The cysteine at codon 642 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
CardioboostArm	Benign	0.00034
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	3.6
DANN	Benign	0.74
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.69	N
PhyloP100		-2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.60
Sift	Benign	0.034	D
Sift4G	Benign	0.062	T
Polyphen		0.82	P
Vest4		0.18
MutPred		0.14		Loss of phosphorylation at T639 (P = 0.1347)
MVP		0.86
MPC		0.70
ClinPred		0.18	T
GERP RS		-0.79
Varity_R		0.15
gMVP		0.64
Mutation Taster		=64/36	polymorphism

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: rs12720454; hg19: chr11-2869128;