rs267605983

Positions:

• chr20-49373357-G-A
• chr20-49373357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004975.4(KCNB1):​c.2203C>T​(p.Pro735Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86

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]

ENSG00000290421 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNB1. . Gene score misZ: 4.269 (greater than the threshold 3.09). Trascript score misZ: 5.3923 (greater than threshold 3.09). The gene has 76 curated pathogenic missense variants (we use a threshold of 10). The gene has 110 curated benign missense variants. GenCC has associacion of the gene with undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09774387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.2203C>T	p.Pro735Ser	missense_variant	2/2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.2203C>T	p.Pro735Ser	missense_variant	3/3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+41333G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.2203C>T	p.Pro735Ser	missense_variant	2/2	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.2203C>T	p.Pro735Ser	missense_variant	3/3	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.97-73974C>T		intron_variant		5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.206+41333G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.83	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.22
Sift	Benign	0.12	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.0	B;B
Vest4		0.043
MutPred		0.33		Loss of catalytic residue at P734 (P = 0.0137);Loss of catalytic residue at P734 (P = 0.0137);
MVP		0.43
MPC		0.19
ClinPred		0.077	T
GERP RS		3.3
Varity_R		0.028
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs267605983; hg19: chr20-47989894;