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chr11-2445102-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000218.3(KCNQ1):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 939,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

2
5
12

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.15
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a region_of_interest Disordered (size 27) in uniprot entity KCNQ1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2445103-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431053.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.4G>A p.Ala2Thr missense_variant 1/16 ENST00000155840.12
KCNQ1NM_001406836.1 linkuse as main transcriptc.4G>A p.Ala2Thr missense_variant 1/15
KCNQ1NM_001406838.1 linkuse as main transcriptc.4G>A p.Ala2Thr missense_variant 1/11
KCNQ1NM_001406837.1 linkuse as main transcriptc.-359G>A 5_prime_UTR_variant 1/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.4G>A p.Ala2Thr missense_variant 1/161 NM_000218.3 P1P51787-1
KCNQ1ENST00000646564.2 linkuse as main transcriptc.4G>A p.Ala2Thr missense_variant 1/11
KCNQ1ENST00000496887.7 linkuse as main transcriptc.24-281G>A intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000213
AC:
2
AN:
939866
Hom.:
0
Cov.:
30
AF XY:
0.00000452
AC XY:
2
AN XY:
442614
show subpopulations
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:
0.00000241
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The KCNQ1 p.Ala2Thr variant was not identified in the literature nor was it identified in dbSNP, ClinVar or in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.Ala2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Benign
-0.10
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.56
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.46
T
M_CAP
Pathogenic
0.99
D
MetaRNN
Uncertain
0.57
D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.13
N
REVEL
Uncertain
0.37
Sift
Benign
0.24
T
Sift4G
Benign
0.64
T
Polyphen
0.074
B
Vest4
0.48
MutPred
0.22
Gain of glycosylation at A2 (P = 0.0113);
MVP
0.91
MPC
1.1
ClinPred
0.30
T
GERP RS
1.6
Varity_R
0.044
gMVP
0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2466332; API