chr2-162396813-A-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_033272.4(KCNH7):c.2540T>A(p.Met847Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
KCNH7
NM_033272.4 missense
NM_033272.4 missense
Scores
7
6
1
Clinical Significance
Conservation
PhyloP100: 9.32
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904
BS2
High AC in GnomAdExome4 at 52 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH7 | NM_033272.4 | c.2540T>A | p.Met847Lys | missense_variant | 11/16 | ENST00000332142.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH7 | ENST00000332142.10 | c.2540T>A | p.Met847Lys | missense_variant | 11/16 | 1 | NM_033272.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151914Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249586Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134896
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1459920Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 726284
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151914Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74174
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | The c.2540T>A (p.M847K) alteration is located in exon 11 (coding exon 11) of the KCNH7 gene. This alteration results from a T to A substitution at nucleotide position 2540, causing the methionine (M) at amino acid position 847 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D
Polyphen
0.97
.;D
Vest4
0.83
MVP
MPC
0.59
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at