chr11-2777991-G-C

Position:

• chr11-2777991-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000218.3(KCNQ1):​c.1748G>C​(p.Arg583Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2777990-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1748G>C	p.Arg583Pro	missense_variant	15/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1748G>C	p.Arg583Pro	missense_variant	15/16	1	NM_000218.3	ENSP00000155840	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Benign	0.040
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D;D;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Pathogenic	0.79
Sift	Benign	0.089	T;.;T;.
Sift4G	Uncertain	0.056	T;.;T;.
Polyphen		0.14	B;.;P;.
Vest4		0.73
MutPred		0.56		Loss of MoRF binding (P = 0.0028);.;.;.;
MVP		0.96
MPC		1.3
ClinPred		0.87	D
GERP RS		3.1
Varity_R		0.34
gMVP		0.97

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: rs199473482; hg19: chr11-2799221;