2-162373516-G-T

Variant names:

• chr2-162373516-G-T
• rs745510969
• NM_033272.4:c.3278C>A

Variant summary

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

The NM_033272.4(KCNH7):​c.3278C>A​(p.Pro1093Gln) 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. 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. P1093L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH7 NM_033272.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 1 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]

GCA (HGNC:15990): (grancalcin) This gene encodes a calcium-binding protein that is abundant in neutrophils and macrophages. In the absence of divalent cation, this protein localizes to the cytosolic fraction; with magnesium alone, it partitions with the granule fraction; and in the presence of magnesium and calcium, it associates with both the granule and membrane fractions. Alternative splicing and use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Aug 2016]

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=0.38221526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH7	NM_033272.4	c.3278C>A	p.Pro1093Gln	missense_variant	Exon 15 of 16	ENST00000332142.10	NP_150375.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH7	ENST00000332142.10	c.3278C>A	p.Pro1093Gln	missense_variant	Exon 15 of 16	1	NM_033272.4	ENSP00000331727.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.37	.;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.4	.;L
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.88	.;P
Vest4		0.28
MutPred		0.36		.;Gain of MoRF binding (P = 0.0428);
MVP		0.56
MPC		0.084
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.35
gMVP		0.44
Mutation Taster		=72/28	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: rs745510969; hg19: chr2-163230026;