1-40784173-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004700.4(KCNQ4):ā€‹c.80C>Gā€‹(p.Thr27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,116,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. T27T) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 32)
Exomes š‘“: 0.000010 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0820
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2784923).
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.80C>G p.Thr27Arg missense_variant Exon 1 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8
KCNQ4NM_172163.3 linkc.80C>G p.Thr27Arg missense_variant Exon 1 of 13 NP_751895.1 P56696-2B3KQH8
KCNQ4XM_047434057.1 linkc.80C>G p.Thr27Arg missense_variant Exon 1 of 13 XP_047290013.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.80C>G p.Thr27Arg missense_variant Exon 1 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.80C>G p.Thr27Arg missense_variant Exon 1 of 13 5 ENSP00000423756.2 P56696-2

Frequencies

GnomAD3 genomes
AF:
0.000102
AC:
15
AN:
147112
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000343
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000151
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
10
AN:
969284
Hom.:
0
Cov.:
19
AF XY:
0.00000854
AC XY:
4
AN XY:
468144
show subpopulations
Gnomad4 AFR exome
AF:
0.000383
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:
0.00000356
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000109
AC:
16
AN:
147222
Hom.:
0
Cov.:
32
AF XY:
0.000112
AC XY:
8
AN XY:
71724
show subpopulations
Gnomad4 AFR
AF:
0.000367
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000151
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000982

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Oct 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.80C>G (p.T27R) alteration is located in exon 1 (coding exon 1) of the KCNQ4 gene. This alteration results from a C to G substitution at nucleotide position 80, causing the threonine (T) at amino acid position 27 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Feb 21, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the KCNQ4 protein (p.Thr27Arg). This variant is present in population databases (no rsID available, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.25
T;T;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.79
.;T;T
M_CAP
Pathogenic
0.95
D
MetaRNN
Benign
0.28
T;T;T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.3
L;L;L
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-0.87
.;N;N
REVEL
Uncertain
0.36
Sift
Benign
0.089
.;T;T
Sift4G
Benign
0.34
.;T;T
Polyphen
0.98
D;D;D
Vest4
0.15, 0.20
MutPred
0.22
Loss of glycosylation at T27 (P = 0.0323);Loss of glycosylation at T27 (P = 0.0323);Loss of glycosylation at T27 (P = 0.0323);
MVP
0.77
MPC
1.6
ClinPred
0.41
T
GERP RS
0.46
Varity_R
0.13
gMVP
0.63

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1001249688; hg19: chr1-41249845; API