2-162373482-G-C

Variant names:

• chr2-162373482-G-C
• rs375047834
• NM_033272.4:c.3312C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033272.4(KCNH7):​c.3312C>G​(p.Ser1104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 1,387,620 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: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: KCNH7 NM_033272.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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]

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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20086104).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH7	NM_033272.4	c.3312C>G	p.Ser1104Arg	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.3312C>G	p.Ser1104Arg	missense_variant	Exon 15 of 16	1	NM_033272.4	ENSP00000331727.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000721 AC: 10 AN: 1387620 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 686986

African (AFR) AF: 0.00 AC: 0 AN: 30494

American (AMR) AF: 0.00 AC: 0 AN: 36056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23104

East Asian (EAS) AF: 0.00 AC: 0 AN: 35874

South Asian (SAS) AF: 0.00 AC: 0 AN: 74200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1073534

Other (OTH) AF: 0.000122 AC: 7 AN: 57348

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3312C>G (p.S1104R) alteration is located in exon 15 (coding exon 15) of the KCNH7 gene. This alteration results from a C to G substitution at nucleotide position 3312, causing the serine (S) at amino acid position 1104 to be replaced by an arginine (R). 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	0.23
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.0	.;M
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	.;N
REVEL	Uncertain	0.58
Sift	Benign	0.058	.;T
Sift4G	Benign	0.54	T;T
Polyphen		0.38	.;B
Vest4		0.21
MutPred		0.23		.;Gain of catalytic residue at S1104 (P = 0.0023);
MVP		0.47
MPC		0.10
ClinPred		0.56	D
GERP RS		4.0
Varity_R		0.11
gMVP		0.51
Mutation Taster		=57/43	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: rs375047834; hg19: chr2-163229992;