rs201212125
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 1P and 17B. PP2BP4BP6_Very_StrongBS1BS2
The NM_004975.4(KCNB1):c.1997C>T(p.Pro666Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,614,000 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
KCNB1
NM_004975.4 missense
NM_004975.4 missense
Scores
1
10
7
Clinical Significance
Conservation
PhyloP100: 6.48
Genes affected
KCNB1 (HGNC:6231): (potassium voltage-gated channel subfamily B member 1) 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KCNB1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.32633734).
BP6
?
Variant 20-49373563-G-A is Benign according to our data. Variant chr20-49373563-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000112 (164/1461850) while in subpopulation MID AF= 0.00225 (13/5768). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4_exome. There are 93 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNB1 | NM_004975.4 | c.1997C>T | p.Pro666Leu | missense_variant | 2/2 | ENST00000371741.6 | |
LOC105372649 | XR_001754659.2 | n.1201+41539G>A | intron_variant, non_coding_transcript_variant | ||||
KCNB1 | XM_011528799.3 | c.1997C>T | p.Pro666Leu | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNB1 | ENST00000371741.6 | c.1997C>T | p.Pro666Leu | missense_variant | 2/2 | 1 | NM_004975.4 | P1 | |
KCNB1 | ENST00000635465.1 | c.1997C>T | p.Pro666Leu | missense_variant | 3/3 | 1 | P1 | ||
ENST00000637341.1 | n.206+41539G>A | intron_variant, non_coding_transcript_variant | 5 | ||||||
KCNB1 | ENST00000635878.1 | c.97-74180C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152150Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000139 AC: 35AN: 251264Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135808
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GnomAD4 exome AF: 0.000112 AC: 164AN: 1461850Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 727230
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74322
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2020 | - - |
Developmental and epileptic encephalopathy, 26 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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