12-49557497-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012284.3(KCNH3):​c.2796C>T​(p.Ser932=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,611,532 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 17 hom., cov: 32)
Exomes 𝑓: 0.00094 ( 18 hom. )

Consequence

KCNH3
NM_012284.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.118
Variant links:
Genes affected
KCNH3 (HGNC:6252): (potassium voltage-gated channel subfamily H member 3) The protein encoded by this gene is a voltage-gated potassium channel alpha subunit predominantly expressed in the forebrain. Studies in mice have found that cognitive function increases when this gene is knocked out. In humans, the encoded protein has been shown to be capable of binding glycoprotein 120 of the human immunodeficiency virus type 1 (HIV-1) envelope. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]
MCRS1 (HGNC:6960): (microspherule protein 1) Enables RNA binding activity and telomerase inhibitor activity. Involved in histone H4 acetylation; negative regulation of DNA metabolic process; and positive regulation of protein localization to nucleolus. Located in cytoplasm; nucleolus; and nucleoplasm. Part of Ino80 complex; MLL1 complex; and histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 12-49557497-C-T is Benign according to our data. Variant chr12-49557497-C-T is described in ClinVar as [Benign]. Clinvar id is 735166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.118 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00883 (1345/152338) while in subpopulation AFR AF= 0.0303 (1259/41576). AF 95% confidence interval is 0.0289. There are 17 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1345 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH3NM_012284.3 linkuse as main transcriptc.2796C>T p.Ser932= synonymous_variant 15/15 ENST00000257981.7 NP_036416.1
KCNH3NM_001314030.2 linkuse as main transcriptc.2616C>T p.Ser872= synonymous_variant 15/15 NP_001300959.1
KCNH3XM_011538085.3 linkuse as main transcriptc.2829C>T p.Ser943= synonymous_variant 15/15 XP_011536387.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH3ENST00000257981.7 linkuse as main transcriptc.2796C>T p.Ser932= synonymous_variant 15/151 NM_012284.3 ENSP00000257981 P1
MCRS1ENST00000551598.5 linkuse as main transcriptc.430-747G>A intron_variant 5 ENSP00000448947
KCNH3ENST00000548675.1 linkuse as main transcriptn.526C>T non_coding_transcript_exon_variant 3/33
KCNH3ENST00000649994.1 linkuse as main transcriptc.*2406C>T 3_prime_UTR_variant, NMD_transcript_variant 16/16 ENSP00000497890

Frequencies

GnomAD3 genomes
AF:
0.00880
AC:
1340
AN:
152220
Hom.:
17
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0303
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00419
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:
0.000118
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00257
AC:
637
AN:
247758
Hom.:
4
AF XY:
0.00198
AC XY:
266
AN XY:
134396
show subpopulations
Gnomad AFR exome
AF:
0.0323
Gnomad AMR exome
AF:
0.00255
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000151
Gnomad OTH exome
AF:
0.00182
GnomAD4 exome
AF:
0.000940
AC:
1372
AN:
1459194
Hom.:
18
Cov.:
33
AF XY:
0.000851
AC XY:
618
AN XY:
726040
show subpopulations
Gnomad4 AFR exome
AF:
0.0314
Gnomad4 AMR exome
AF:
0.00260
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000495
Gnomad4 OTH exome
AF:
0.00210
GnomAD4 genome
AF:
0.00883
AC:
1345
AN:
152338
Hom.:
17
Cov.:
32
AF XY:
0.00899
AC XY:
670
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0303
Gnomad4 AMR
AF:
0.00418
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00253
Hom.:
1
Bravo
AF:
0.0104
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

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

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 10, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Benign
3.1
DANN
Benign
0.80

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: rs77998597; hg19: chr12-49951280; API