12-49548927-A-T

Position:

• chr12-49548927-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012284.3(KCNH3):​c.1222A>T​(p.Thr408Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000902 in 1,441,492 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: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: KCNH3 NM_012284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12542802).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH3	NM_012284.3	c.1222A>T	p.Thr408Ser	missense_variant	8/15	ENST00000257981.7	NP_036416.1
KCNH3	NM_001314030.2	c.1042A>T	p.Thr348Ser	missense_variant	8/15		NP_001300959.1
KCNH3	XM_011538085.3	c.1222A>T	p.Thr408Ser	missense_variant	8/15		XP_011536387.1
KCNH3	XM_047428613.1	c.1222A>T	p.Thr408Ser	missense_variant	8/10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7	c.1222A>T	p.Thr408Ser	missense_variant	8/15	1	NM_012284.3	ENSP00000257981.5
KCNH3	ENST00000649994.1	n.*832A>T		non_coding_transcript_exon_variant	9/16			ENSP00000497890.1
KCNH3	ENST00000649994.1	n.*832A>T		3_prime_UTR_variant	9/16			ENSP00000497890.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000902 AC: 13 AN: 1441492 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715478

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: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 11, 2022

The c.1222A>T (p.T408S) alteration is located in exon 8 (coding exon 8) of the KCNH3 gene. This alteration results from a A to T substitution at nucleotide position 1222, causing the threonine (T) at amino acid position 408 to be replaced by a serine (S). 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	0.17
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.20	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.51
Sift	Benign	0.96	T
Sift4G	Benign	0.86	T
Polyphen		0.025	B
Vest4		0.18
MutPred		0.47		Gain of disorder (P = 0.022);
MVP		0.86
MPC		1.1
ClinPred		0.26	T
GERP RS		4.0
Varity_R		0.094
gMVP		0.73

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: rs1312799342; hg19: chr12-49942710;