3-19253869-A-T

Variant names:

• chr3-19253869-A-T
• rs199638242
• NM_144633.3:c.292A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144633.3(KCNH8):​c.292A>T​(p.Met98Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M98V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH8 NM_144633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.31
• Publications: 0 publications found

Genes affected

KCNH8 (HGNC:18864): (potassium voltage-gated channel subfamily H member 8) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31550214).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144633.3. 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
	KCNH8	NM_144633.3	MANE Select	c.292A>T	p.Met98Leu	missense	Exon 2 of 16	NP_653234.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH8	ENST00000328405.7	TSL:1 MANE Select	c.292A>T	p.Met98Leu	missense	Exon 2 of 16	ENSP00000328813.2	Q96L42-1
	KCNH8	ENST00000452398.5	TSL:1	n.292A>T		non_coding_transcript_exon	Exon 2 of 16	ENSP00000412141.1	F8WCG6
	KCNH8	ENST00000938024.1		c.292A>T	p.Met98Leu	missense	Exon 2 of 14	ENSP00000608083.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.033
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	-1.3	N
PhyloP100		5.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.56
Sift	Benign	0.87	T
Sift4G	Benign	0.47	T
Polyphen		0.050	B
Vest4		0.55
MutPred		0.39		Loss of methylation at K102 (P = 0.1142)
MVP		0.76
MPC		0.043
ClinPred		0.64	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.47
Mutation Taster		=62/38	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: rs199638242; hg19: chr3-19295361;