Genetic Variant NM_012284.3:c.939A>G (chr12-49544030-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.23

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]

KCNH3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3 link	c.939A>G	p.Ala313Ala	synonymous_variant	Exon 6 of 15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 link	c.759A>G	p.Ala253Ala	synonymous_variant	Exon 6 of 15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 link	c.939A>G	p.Ala313Ala	synonymous_variant	Exon 6 of 15		XP_011536387.1
KCNH3	XM_047428613.1 link	c.939A>G	p.Ala313Ala	synonymous_variant	Exon 6 of 10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7 link	c.939A>G	p.Ala313Ala	synonymous_variant	Exon 6 of 15	1	NM_012284.3	ENSP00000257981.5		Q9ULD8

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40511

AN:

152038

Hom.:

7179

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.185

AC:

46522

AN:

251438

Hom.:

5444

AF XY:

0.180

AC XY:

24463

AN XY:

135896

show subpopulations

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 SAS exome

AF:

0.166

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.:

AF XY:

0.177

AC XY:

128527

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.530

Gnomad4 AMR exome

AF:

0.146

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.0894

Gnomad4 SAS exome

AF:

0.163

Gnomad4 FIN exome

AF:

0.172

Gnomad4 NFE exome

AF:

0.173

Gnomad4 OTH exome

AF:

0.190

GnomAD4 genome

AF:

0.267

AC:

40620

AN:

152156

Hom.:

7221

Cov.:

AF XY:

0.262

AC XY:

19525

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.515

Gnomad4 AMR

AF:

0.185

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.0901

Gnomad4 SAS

AF:

0.159

Gnomad4 FIN

AF:

0.167

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.248

Alfa

AF:

0.199

Hom.:

5034

Bravo

AF:

0.277

Asia WGS

AF:

0.182

AC:

635

AN:

3478

EpiCase

AF:

0.168

EpiControl

AF:

0.170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 15, 2020

GeneDx

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

-0.93

CADD

Benign

0.70

DANN

Benign

0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over