chr1-40824159-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004700.4(KCNQ4):​c.1193A>G​(p.Glu398Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000357 in 1,570,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.39

Publications

0 publications found
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]
KCNQ4 Gene-Disease associations (from GenCC):
  • autosomal dominant nonsyndromic hearing loss 2A
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hearing loss disorder
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.1193A>G p.Glu398Gly missense_variant Exon 9 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.1193A>G p.Glu398Gly missense_variant Exon 9 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000506017.1 linkn.512A>G non_coding_transcript_exon_variant Exon 6 of 11 2
KCNQ4ENST00000509682.6 linkc.1130+1757A>G intron_variant Intron 8 of 12 5 ENSP00000423756.2 P56696-2
KCNQ4ENST00000443478.3 linkc.815+1757A>G intron_variant Intron 7 of 12 5 ENSP00000406735.3 H0Y6N7

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000284
AC:
5
AN:
175816
AF XY:
0.0000104
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000702
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000339
AC:
48
AN:
1417962
Hom.:
0
Cov.:
33
AF XY:
0.0000371
AC XY:
26
AN XY:
701628
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32292
American (AMR)
AF:
0.00
AC:
0
AN:
38624
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25402
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36934
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80872
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49186
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5424
European-Non Finnish (NFE)
AF:
0.0000422
AC:
46
AN:
1090594
Other (OTH)
AF:
0.0000341
AC:
2
AN:
58634
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74310
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.0000654
AC:
1
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.00000862
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 05, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Glu398Gly variant in KCNQ4 has not been previously reported in individuals with hearing loss and data from large population studies are insufficient to as sess the frequency of this variant. Glutamate (Glu) at position 398 is not conse rved in mammals or evolutionarily distant species and 1 mammal (domestic goat) c arries a glycine (Gly), supporting that this change may be tolerated. Additiona l computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu398Gly variant is uncertain. -

Inborn genetic diseases Uncertain:1
Oct 03, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1193A>G (p.E398G) alteration is located in exon 9 (coding exon 9) of the KCNQ4 gene. This alteration results from a A to G substitution at nucleotide position 1193, causing the glutamic acid (E) at amino acid position 398 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal dominant nonsyndromic hearing loss 2A Uncertain:1
Apr 11, 2023
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Feb 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 398 of the KCNQ4 protein (p.Glu398Gly). This variant is present in population databases (rs773975779, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. ClinVar contains an entry for this variant (Variation ID: 228769). 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. 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
Benign
0.31
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.64
.;T
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Benign
1.5
L;L
PhyloP100
4.4
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.6
.;N
REVEL
Uncertain
0.52
Sift
Benign
0.33
.;T
Sift4G
Benign
0.39
.;T
Polyphen
0.98
D;D
Vest4
0.49
MutPred
0.28
Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);
MVP
0.91
MPC
0.16
ClinPred
0.38
T
GERP RS
5.7
Varity_R
0.18
gMVP
0.60
Mutation Taster
=80/20
polymorphism

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

Other links and lift over

dbSNP: rs773975779; hg19: chr1-41289831; API