chr12-49544306-G-T

Variant names:

• chr12-49544306-G-T
• rs770307418
• NM_012284.3:c.1113G>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_012284.3(KCNH3):​c.1113G>T​(p.Ala371Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNH3 NM_012284.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.225

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=-0.225 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.1113G>T	p.Ala371Ala	synonymous_variant	Exon 7 of 15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.933G>T	p.Ala311Ala	synonymous_variant	Exon 7 of 15		NP_001300959.1
KCNH3	XM_011538085.3	c.1113G>T	p.Ala371Ala	synonymous_variant	Exon 7 of 15		XP_011536387.1
KCNH3	XM_047428613.1	c.1113G>T	p.Ala371Ala	synonymous_variant	Exon 7 of 10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7	c.1113G>T	p.Ala371Ala	synonymous_variant	Exon 7 of 15	1	NM_012284.3	ENSP00000257981.5
KCNH3	ENST00000551415.1	n.53G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
KCNH3	ENST00000649994.1	n.*723G>T		non_coding_transcript_exon_variant	Exon 8 of 16			ENSP00000497890.1
KCNH3	ENST00000649994.1	n.*723G>T		3_prime_UTR_variant	Exon 8 of 16			ENSP00000497890.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460728 Hom.: 0 Cov.: 37 AF XY: 0.0000138 AC XY: 10 AN XY: 726730

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: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.8
DANN	Benign	0.83

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: rs770307418; hg19: chr12-49938089; COSMIC: COSV57792330; COSMIC: COSV57792330;