rs146556660

Variant names:

• chr12-49557505-T-A
• rs146556660
• NM_012284.3:c.2804T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012284.3(KCNH3):​c.2804T>A​(p.Leu935Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,611,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37
• Publications: 0 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]

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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 12 AD gene.

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.2804T>A	p.Leu935Gln	missense	Exon 15 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.2624T>A	p.Leu875Gln	missense	Exon 15 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.2804T>A	p.Leu935Gln	missense	Exon 15 of 15	ENSP00000257981.5	Q9ULD8
	KCNH3	ENST00000965158.1		c.2570T>A	p.Leu857Gln	missense	Exon 14 of 14	ENSP00000635217.1
	MCRS1	ENST00000551598.5	TSL:5	c.430-755A>T		intron	N/A	ENSP00000448947.1	H0YIA0

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000177 AC: 44 AN: 248528 AF XY: 0.000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1459472 Hom.: 0 Cov.: 33 AF XY: 0.000207 AC XY: 150 AN XY: 726156

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000224 AC: 10 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000782 AC: 4 AN: 51178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000261 AC: 290 AN: 1111920

Other (OTH) AF: 0.000265 AC: 16 AN: 60356

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41598

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.55	N
PhyloP100		3.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.022	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.59
MVP		0.94
MPC		0.51
ClinPred		0.10	T
GERP RS		4.9
Varity_R		0.23
gMVP		0.53
Mutation Taster		=73/27	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

Other links and lift over

dbSNP: rs146556660; hg19: chr12-49951288;