Genetic Variant KCNH7:p.Ile1084Leu (chr2-162373544-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033272.4(KCNH7):c.3250A>C(p.Ile1084Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. I1084V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNH7
NM_033272.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.83

Publications

0 publications found

Variant links:

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 links:

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]

GCA links:

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ACMG classification

Classification was made for transcript

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=0.040784925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH7	NM_033272.4 link	c.3250A>C	p.Ile1084Leu	missense_variant	Exon 15 of 16	ENST00000332142.10	NP_150375.2	Q9NS40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH7	ENST00000332142.10 link	c.3250A>C	p.Ile1084Leu	missense_variant	Exon 15 of 16	1	NM_033272.4	ENSP00000331727.5		Q9NS40-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439350

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32218

American (AMR)

AF:

0.00

AC:

AN:

41236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25754

East Asian (EAS)

AF:

0.00

AC:

AN:

37984

South Asian (SAS)

AF:

0.00

AC:

AN:

82774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101000

Other (OTH)

AF:

0.00

AC:

AN:

59522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.035

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.045

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.34

.;N

PhyloP100

-1.8

PrimateAI

Benign

0.24

PROVEAN

Benign

0.020

.;N

REVEL

Benign

0.17

Sift

Benign

1.0

.;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0090

.;B

Vest4

0.16

MutPred

0.33

.;Gain of phosphorylation at Y1080 (P = 0.1009);

MVP

0.42

MPC

0.090

ClinPred

0.031

GERP RS

-3.5

Varity_R

0.050

gMVP

0.12

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over