chr12-49544030-A-G

Variant names:

• chr12-49544030-A-G
• rs1150057
• NM_012284.3:c.939A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012284.3(KCNH3):​c.939A>G​(p.Ala313Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,434 control chromosomes in the GnomAD database, including 33,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7221 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25877 hom.)
• Consequence: KCNH3 NM_012284.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.23
• Publications: 14 publications found

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]

KCNH3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-49544030-A-G is Benign according to our data. Variant chr12-49544030-A-G is described in ClinVar as Benign. ClinVar VariationId is 1290430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH3	NM_012284.3	MANE Select	c.939A>G	p.Ala313Ala	synonymous	Exon 6 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.759A>G	p.Ala253Ala	synonymous	Exon 6 of 15	NP_001300959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH3	ENST00000257981.7	TSL:1 MANE Select	c.939A>G	p.Ala313Ala	synonymous	Exon 6 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.705A>G	p.Ala235Ala	synonymous	Exon 5 of 14	ENSP00000635217.1
	KCNH3	ENST00000649994.1		n.*549A>G		non_coding_transcript_exon	Exon 7 of 16	ENSP00000497890.1	A0A3B3ITH0

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40511 AN: 152038 Hom.: 7179 Cov.: 33

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.185 AC: 46522 AN: 251438 AF XY: 0.180

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.179 AC: 261006 AN: 1461278 Hom.: 25877 Cov.: 42 AF XY: 0.177 AC XY: 128527 AN XY: 726812

African (AFR) AF: 0.530 AC: 17742 AN: 33480

American (AMR) AF: 0.146 AC: 6534 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4886 AN: 26130

East Asian (EAS) AF: 0.0894 AC: 3547 AN: 39674

South Asian (SAS) AF: 0.163 AC: 14051 AN: 86240

European-Finnish (FIN) AF: 0.172 AC: 9199 AN: 53410

Middle Eastern (MID) AF: 0.180 AC: 1039 AN: 5766

European-Non Finnish (NFE) AF: 0.173 AC: 192547 AN: 1111480

Other (OTH) AF: 0.190 AC: 11461 AN: 60378

GnomAD4 genome AF: 0.267 AC: 40620 AN: 152156 Hom.: 7221 Cov.: 33 AF XY: 0.262 AC XY: 19525 AN XY: 74398

African (AFR) AF: 0.515 AC: 21391 AN: 41500

American (AMR) AF: 0.185 AC: 2832 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3468

East Asian (EAS) AF: 0.0901 AC: 467 AN: 5184

South Asian (SAS) AF: 0.159 AC: 770 AN: 4830

European-Finnish (FIN) AF: 0.167 AC: 1764 AN: 10586

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12010 AN: 67976

Other (OTH) AF: 0.248 AC: 522 AN: 2108

Alfa AF: 0.199 Hom.: 6435

Bravo AF: 0.277

Asia WGS AF: 0.182 AC: 635 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.170

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.70
DANN	Benign	0.46
PhyloP100		-4.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1150057; hg19: chr12-49937813; COSMIC: COSV57790854; COSMIC: COSV57790854;