11-2662023-G-C

Position:

• chr11-2662023-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000218.3(KCNQ1):​c.1456G>C​(p.Ala486Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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]

KCNQ1OT1 (HGNC:6295): (KCNQ1 opposite strand/antisense transcript 1) Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1456G>C	p.Ala486Pro	missense_variant	11/16	ENST00000155840.12	NP_000209.2
KCNQ1OT1	NR_002728.3	n.37976C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1456G>C	p.Ala486Pro	missense_variant	11/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1OT1	ENST00000710656.1	n.376-20908C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2015

In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases and has not been reported in the literature. This sequence change replaces alanine with proline at codon 486 of the KCNQ1 protein (p.Ala486Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Pathogenic	0.69
Sift	Benign	0.045	D;.;T
Sift4G	Benign	0.15	T;.;T
Polyphen		0.98	D;.;B
Vest4		0.55
MutPred		0.67		Gain of disorder (P = 0.0197);.;.;
MVP		0.94
MPC		1.3
ClinPred		0.28	T
GERP RS		1.5
Varity_R		0.36
gMVP		0.48

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: rs753256800; hg19: chr11-2683253;