chr12-49557847-G-A

Position:

• chr12-49557847-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000257981.7(KCNH3):​c.3146G>A​(p.Gly1049Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,214 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNH3 ENST00000257981.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33840007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.3146G>A	p.Gly1049Glu	missense_variant	15/15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.2966G>A	p.Gly989Glu	missense_variant	15/15		NP_001300959.1
KCNH3	XM_011538085.3	c.3179G>A	p.Gly1060Glu	missense_variant	15/15		XP_011536387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7	c.3146G>A	p.Gly1049Glu	missense_variant	15/15	1	NM_012284.3	ENSP00000257981.5
MCRS1	ENST00000551598.5	c.429+996C>T		intron_variant		5		ENSP00000448947.1
KCNH3	ENST00000649994.1	n.*2756G>A		non_coding_transcript_exon_variant	16/16			ENSP00000497890.1
KCNH3	ENST00000649994.1	n.*2756G>A		3_prime_UTR_variant	16/16			ENSP00000497890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442214 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714882

Gnomad4 AFR exome AF: 0.00

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.3146G>A (p.G1049E) alteration is located in exon 15 (coding exon 15) of the KCNH3 gene. This alteration results from a G to A substitution at nucleotide position 3146, causing the glycine (G) at amino acid position 1049 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.81	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.37
Sift	Benign	0.051	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.31		Loss of catalytic residue at S1048 (P = 0.0265);
MVP		0.71
MPC		0.20
ClinPred		0.79	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.13

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: rs867584076; hg19: chr12-49951630; COSMIC: COSV57790350; COSMIC: COSV57790350;