20-49393138-G-T

Variant names:

• chr20-49393138-G-T
• rs6125642
• NM_004975.4:c.568-18146C>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.568-18146C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 151,848 control chromosomes in the GnomAD database, including 14,525 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 0.43 (14525 hom., cov: 31)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004975.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	NM_004975.4	MANE Select	c.568-18146C>A		intron	N/A	NP_004966.1	Q14721

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.568-18146C>A		intron	N/A	ENSP00000360806.3	Q14721
	KCNB1	ENST00000635465.1	TSL:1	c.568-18146C>A		intron	N/A	ENSP00000489193.1	Q14721
	KCNB1	ENST00000635878.1	TSL:5	c.96+88776C>A		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes AF: 0.435 AC: 65948 AN: 151730 Hom.: 14486 Cov.: 31

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.435 AC: 66050 AN: 151848 Hom.: 14525 Cov.: 31 AF XY: 0.437 AC XY: 32429 AN XY: 74230

African (AFR) AF: 0.441 AC: 18252 AN: 41386

American (AMR) AF: 0.456 AC: 6954 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1014 AN: 3468

East Asian (EAS) AF: 0.577 AC: 2968 AN: 5146

South Asian (SAS) AF: 0.398 AC: 1915 AN: 4814

European-Finnish (FIN) AF: 0.492 AC: 5181 AN: 10534

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28322 AN: 67932

Other (OTH) AF: 0.421 AC: 887 AN: 2108

Alfa AF: 0.420 Hom.: 1718

Bravo AF: 0.435

Asia WGS AF: 0.488 AC: 1700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.055
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: rs6125642; hg19: chr20-48009675;