chr20-49399672-T-C

Variant names:

• chr20-49399672-T-C
• rs6063397
• NM_004975.4:c.568-24680A>G

Variant summary

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

The NM_004975.4(KCNB1):​c.568-24680A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 151,946 control chromosomes in the GnomAD database, including 13,094 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 0.41 (13094 hom., cov: 31)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.204
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.568-24680A>G		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.568-24680A>G		intron_variant	Intron 2 of 2		XP_011527101.1
LOC105372649	XR_001754659.2	n.1202-26980T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.568-24680A>G		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.568-24680A>G		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+82242A>G		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.207-23420T>C		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62178 AN: 151828 Hom.: 13065 Cov.: 31

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.410 AC: 62265 AN: 151946 Hom.: 13094 Cov.: 31 AF XY: 0.413 AC XY: 30680 AN XY: 74246

African (AFR) AF: 0.342 AC: 14166 AN: 41428

American (AMR) AF: 0.450 AC: 6870 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3470

East Asian (EAS) AF: 0.579 AC: 2993 AN: 5168

South Asian (SAS) AF: 0.401 AC: 1930 AN: 4816

European-Finnish (FIN) AF: 0.500 AC: 5275 AN: 10540

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28611 AN: 67938

Other (OTH) AF: 0.398 AC: 841 AN: 2114

Alfa AF: 0.405 Hom.: 7749

Bravo AF: 0.406

Asia WGS AF: 0.492 AC: 1712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.65
PhyloP100		-0.20
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: rs6063397; hg19: chr20-48016209;