1-40784135-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_004700.4(KCNQ4):​c.42G>T​(p.Pro14Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 976,386 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 1 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.797
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 Benign. Variant got -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
Variant 1-40784135-G-T is Benign according to our data. Variant chr1-40784135-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3705129.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.797 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000313 (26/831648) while in subpopulation MID AF= 0.00164 (3/1828). AF 95% confidence interval is 0.000447. There are 1 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 12. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.42G>T p.Pro14Pro synonymous_variant Exon 1 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8
KCNQ4NM_172163.3 linkc.42G>T p.Pro14Pro synonymous_variant Exon 1 of 13 NP_751895.1 P56696-2B3KQH8
KCNQ4XM_047434057.1 linkc.42G>T p.Pro14Pro synonymous_variant Exon 1 of 13 XP_047290013.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.42G>T p.Pro14Pro synonymous_variant Exon 1 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.42G>T p.Pro14Pro synonymous_variant Exon 1 of 13 5 ENSP00000423756.2 P56696-2

Frequencies

GnomAD3 genomes
AF:
0.0000553
AC:
8
AN:
144738
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000296
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000107
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000360
AC:
6
AN:
16682
Hom.:
1
AF XY:
0.000295
AC XY:
3
AN XY:
10160
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00120
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000488
Gnomad OTH exome
AF:
0.00192
GnomAD4 exome
AF:
0.0000313
AC:
26
AN:
831648
Hom.:
1
Cov.:
12
AF XY:
0.0000301
AC XY:
12
AN XY:
398264
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000272
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000257
Gnomad4 OTH exome
AF:
0.0000708
GnomAD4 genome
AF:
0.0000553
AC:
8
AN:
144738
Hom.:
0
Cov.:
32
AF XY:
0.0000284
AC XY:
2
AN XY:
70390
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000296
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000107
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Mar 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
13
DANN
Benign
0.88

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: rs749544977; hg19: chr1-41249807; API