chr2-162379988-T-C

Variant names:

• chr2-162379988-T-C
• NM_033272.4:c.2996A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033272.4(KCNH7):​c.2996A>G​(p.Asn999Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH7 NM_033272.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

Genes affected

KCNH7 (HGNC:18863): (potassium voltage-gated channel subfamily H member 7) 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. There are at least two alternatively spliced transcript variants derived from this gene and encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KCNH7 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06590909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH7	NM_033272.4	c.2996A>G	p.Asn999Ser	missense_variant	Exon 14 of 16	ENST00000332142.10	NP_150375.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH7	ENST00000332142.10	c.2996A>G	p.Asn999Ser	missense_variant	Exon 14 of 16	1	NM_033272.4	ENSP00000331727.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2996A>G (p.N999S) alteration is located in exon 14 (coding exon 14) of the KCNH7 gene. This alteration results from a A to G substitution at nucleotide position 2996, causing the asparagine (N) at amino acid position 999 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	0.075
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.0	.;L
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.080	.;N
REVEL	Benign	0.24
Sift	Benign	0.54	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.21
MutPred		0.17		.;Gain of phosphorylation at N999 (P = 0.0092);
MVP		0.47
MPC		0.072
ClinPred		0.19	T
GERP RS		3.5
Varity_R		0.036
gMVP		0.085
Mutation Taster		=95/5	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

hg19: chr2-163236498;