12-49557497-C-T

Variant names:

• chr12-49557497-C-T
• rs77998597
• NM_012284.3:c.2796C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012284.3(KCNH3):​c.2796C>T​(p.Ser932Ser) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.118

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]

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1345 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.2796C>T	p.Ser932Ser	synonymous_variant	Exon 15 of 15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.2616C>T	p.Ser872Ser	synonymous_variant	Exon 15 of 15		NP_001300959.1
KCNH3	XM_011538085.3	c.2829C>T	p.Ser943Ser	synonymous_variant	Exon 15 of 15		XP_011536387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7	c.2796C>T	p.Ser932Ser	synonymous_variant	Exon 15 of 15	1	NM_012284.3	ENSP00000257981.5

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1340 AN: 152220 Hom.: 17 Cov.: 32

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

GnomAD2 exomes AF: 0.00257 AC: 637 AN: 247758 AF XY: 0.00198

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 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

Gnomad4 AFR exome AF: 0.0314 AC: 1051 AN: 33474

Gnomad4 AMR exome AF: 0.00260 AC: 116 AN: 44694

Gnomad4 ASJ exome AF: 0.000115 AC: 3 AN: 26104

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.0000928 AC: 8 AN: 86228

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51056

Gnomad4 NFE exome AF: 0.0000495 AC: 55 AN: 1111840

Gnomad4 Remaining exome AF: 0.00210 AC: 127 AN: 60340

GnomAD4 genome AF: 0.00883 AC: 1345 AN: 152338 Hom.: 17 Cov.: 32 AF XY: 0.00899 AC XY: 670 AN XY: 74494

Gnomad4 AFR AF: 0.0303 AC: 0.0302819 AN: 0.0302819

Gnomad4 AMR AF: 0.00418 AC: 0.00418082 AN: 0.00418082

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000118 AC: 0.000117612 AN: 0.000117612

Gnomad4 OTH AF: 0.00662 AC: 0.00661626 AN: 0.00661626

Alfa AF: 0.00294 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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.1
DANN	Benign	0.80
Mutation Taster		=100/0	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

LitVar

Other links and lift over

dbSNP: rs77998597; hg19: chr12-49951280;