chr1-40784158-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004700.4(KCNQ4):​c.65A>C​(p.Glu22Ala) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KCNQ4
NM_004700.4 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.745
Variant links:
Genes affected
KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

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=0.23750868).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ4NM_004700.4 linkuse as main transcriptc.65A>C p.Glu22Ala missense_variant 1/14 ENST00000347132.10
KCNQ4NM_172163.3 linkuse as main transcriptc.65A>C p.Glu22Ala missense_variant 1/13
KCNQ4XM_047434057.1 linkuse as main transcriptc.65A>C p.Glu22Ala missense_variant 1/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ4ENST00000347132.10 linkuse as main transcriptc.65A>C p.Glu22Ala missense_variant 1/141 NM_004700.4 P2P56696-1
KCNQ4ENST00000509682.6 linkuse as main transcriptc.65A>C p.Glu22Ala missense_variant 1/135 A1P56696-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
16
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 16, 2021The c.65A>C (p.E22A) alteration is located in exon 1 (coding exon 1) of the KCNQ4 gene. This alteration results from a A to C substitution at nucleotide position 65, causing the glutamic acid (E) at amino acid position 22 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.0091
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Benign
0.51
DEOGEN2
Benign
0.20
T;T;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.80
.;T;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Uncertain
0.50
D
MutationAssessor
Benign
1.7
L;L;L
MutationTaster
Benign
0.98
D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-0.76
.;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.74
.;T;T
Sift4G
Benign
0.75
.;T;T
Polyphen
0.0010
B;B;B
Vest4
0.15, 0.22
MutPred
0.21
Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP
0.60
MPC
1.9
ClinPred
0.44
T
GERP RS
1.7
Varity_R
0.067
gMVP
0.60

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: chr1-41249830; API