chr11-2847898-C-G

Position:

• chr11-2847898-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C642C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.52

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20488328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1926C>G	p.Cys642Trp	missense_variant	16/16	ENST00000155840.12	NP_000209.2
KCNQ1-AS1	NR_130721.1	n.778-7456G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1926C>G	p.Cys642Trp	missense_variant	16/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7456G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 23, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
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;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.86	N;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.034	D;T;.
Sift4G	Benign	0.062	T;D;.
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

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: rs12720454; hg19: chr11-2869128;