rs237458

Variant names:

• chr20-49415012-G-A
• rs237458
• NM_004975.4:c.568-40020C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004975.4(KCNB1):​c.568-40020C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,976 control chromosomes in the GnomAD database, including 22,618 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22618 hom., cov: 32)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 1 publications found

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]

KCNB1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 26

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000290421 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.568-40020C>T		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.568-40020C>T		intron_variant	Intron 2 of 2		XP_011527101.1
LOC105372649	XR_001754659.2	n.1202-11640G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.568-40020C>T		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.568-40020C>T		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+66902C>T		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.207-8080G>A		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80204 AN: 151856 Hom.: 22587 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.540

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.528 AC: 80286 AN: 151976 Hom.: 22618 Cov.: 32 AF XY: 0.525 AC XY: 38989 AN XY: 74268

African (AFR) AF: 0.735 AC: 30459 AN: 41456

American (AMR) AF: 0.567 AC: 8667 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1870 AN: 3468

East Asian (EAS) AF: 0.464 AC: 2391 AN: 5158

South Asian (SAS) AF: 0.444 AC: 2135 AN: 4810

European-Finnish (FIN) AF: 0.387 AC: 4080 AN: 10546

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29104 AN: 67940

Other (OTH) AF: 0.536 AC: 1132 AN: 2110

Alfa AF: 0.500 Hom.: 2600

Bravo AF: 0.549

Asia WGS AF: 0.494 AC: 1715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.24
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs237458; hg19: chr20-48031549;