chr11-2445100-T-A

Variant names:

• chr11-2445100-T-A
• rs199473485
• NM_000218.3:c.2T>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.379

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 48 pathogenic variants. Next in-frame start position is after 159 codons. Genomic position: 2528016. Lost 0.234 part of the original CDS.
• PS1: Another start lost variant in NM_000218.3 (KCNQ1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2445100-T-A is Pathogenic according to our data. Variant chr11-2445100-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 488859.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.2T>A	p.Met1?	start_lost	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.2T>A	p.Met1?	start_lost	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.2T>A	p.Met1?	start_lost	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-361T>A		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.2T>A	p.Met1?	start_lost	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000646564.2	c.2T>A	p.Met1?	start_lost	Exon 1 of 11			ENSP00000495806.2
KCNQ1	ENST00000496887.7	c.24-283T>A		intron_variant	Intron 1 of 15	5		ENSP00000434560.2
KCNQ1	ENST00000345015.4	n.-222T>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 936200 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 440548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 03, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Although the c.2 T>A pathogenic variant in the KCNQ1 gene has not been published to our knowledge, another pathogenic variant affecting the same nucleotide, c.2 T>C, has been reported previously in association with JLNS and LQTS (Wang et al., 2011; Gao et al., 2016). Wang et al. (2011) reported c.2 T>C, situated on opposite KCNQ1 alleles (in trans) from a pathogenic frameshift variant, in one individual with JLNS. This individual's father, who was asymptomatic but had a borderline prolonged QTc interval, also harbored c.2 T>C (Wang et al., 2011). Subsequently, Gao et al (2015) identified c.2 T>C in three Chinese individuals with LQTS, and reported it was absent in at least 100 ethnically matched, healthy control alleles. Data from control individuals was not available to assess whether c.2 T>A may be a common benign variant in the general population. Both the c.2 T>A variant and the c.2 T>C variant alter the initiator Methionine residue of KCNQ1. Western blot studies showed that c.2 T>C may cause an alternate translation initiation site downstream and yields a truncated protein that is missing the initial 158 amino acid residues of the KCNQ1 protein (Wang et al., 2011). Additional functional studies showed that while the c.2 T>C variant does not demonstrate a dominant negative effect when co-expressed with wild type protein, it does result in loss of function of the KCNQ1 channel due to a trafficking defect (Wang et al., 2011).In summary, c.2 T>A in the KCNQ1 gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.084	B
Vest4		0.39
MutPred		0.96		Gain of ubiquitination at M1 (P = 0.0177);
MVP		0.95
ClinPred		0.79	D
GERP RS		2.1
Varity_R		0.91
gMVP		0.67

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: rs199473485; hg19: chr11-2466330;