2-162373516-G-A
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_033272.4(KCNH7):c.3278C>T(p.Pro1093Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,575,794 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: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
KCNH7
NM_033272.4 missense
NM_033272.4 missense
Scores
1
7
6
Clinical Significance
Conservation
PhyloP100: 3.02
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 -5 ACMG points.
PP2
Missense variant where missense usually causes diseases, KCNH7
BP4
Computational evidence support a benign effect (MetaRNN=0.233598).
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH7 | NM_033272.4 | c.3278C>T | p.Pro1093Leu | missense_variant | 15/16 | ENST00000332142.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH7 | ENST00000332142.10 | c.3278C>T | p.Pro1093Leu | missense_variant | 15/16 | 1 | NM_033272.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000180 AC: 4AN: 222598Hom.: 0 AF XY: 0.0000248 AC XY: 3AN XY: 120908
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GnomAD4 exome AF: 0.0000105 AC: 15AN: 1423708Hom.: 0 Cov.: 31 AF XY: 0.00000565 AC XY: 4AN XY: 707608
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74272
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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 | Nov 17, 2023 | The c.3278C>T (p.P1093L) alteration is located in exon 15 (coding exon 15) of the KCNH7 gene. This alteration results from a C to T substitution at nucleotide position 3278, causing the proline (P) at amino acid position 1093 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Benign
T
Sift4G
Uncertain
D;D
Polyphen
0.52
.;P
Vest4
0.22
MutPred
0.37
.;Loss of disorder (P = 0.0612);
MVP
MPC
0.095
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