chr20-49416666-C-T

Variant names:

• chr20-49416666-C-T
• rs237462
• NM_004975.4:c.568-41674G>A

Variant summary

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

The NM_004975.4(KCNB1):​c.568-41674G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,968 control chromosomes in the GnomAD database, including 9,885 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 0.36 (9885 hom., cov: 31)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.506
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.568-41674G>A		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.568-41674G>A		intron_variant	Intron 2 of 2		XP_011527101.1
LOC105372649	XR_001754659.2	n.1202-9986C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.568-41674G>A		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.568-41674G>A		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+65248G>A		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.207-6426C>T		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54268 AN: 151848 Hom.: 9876 Cov.: 31

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.357 AC: 54303 AN: 151968 Hom.: 9885 Cov.: 31 AF XY: 0.358 AC XY: 26606 AN XY: 74294

African (AFR) AF: 0.333 AC: 13780 AN: 41428

American (AMR) AF: 0.482 AC: 7374 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1570 AN: 3464

East Asian (EAS) AF: 0.406 AC: 2095 AN: 5160

South Asian (SAS) AF: 0.343 AC: 1649 AN: 4808

European-Finnish (FIN) AF: 0.314 AC: 3320 AN: 10558

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.344 AC: 23355 AN: 67954

Other (OTH) AF: 0.402 AC: 846 AN: 2106

Alfa AF: 0.354 Hom.: 40583

Bravo AF: 0.370

Asia WGS AF: 0.383 AC: 1329 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		-0.51
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: rs237462; hg19: chr20-48033203;