NM_004975.4:c.568-35880G>A

Variant names:

• chr20-49410872-C-T
• rs6125646
• NM_004975.4:c.568-35880G>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.568-35880G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 152,040 control chromosomes in the GnomAD database, including 14,092 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 (14092 hom., cov: 32)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	NM_004975.4	MANE Select	c.568-35880G>A		intron	N/A	NP_004966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.568-35880G>A		intron	N/A	ENSP00000360806.3
	KCNB1	ENST00000635465.1	TSL:1	c.568-35880G>A		intron	N/A	ENSP00000489193.1
	KCNB1	ENST00000635878.1	TSL:5	c.96+71042G>A		intron	N/A	ENSP00000489908.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65507 AN: 151922 Hom.: 14075 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.431 AC: 65572 AN: 152040 Hom.: 14092 Cov.: 32 AF XY: 0.430 AC XY: 31960 AN XY: 74318

African (AFR) AF: 0.415 AC: 17216 AN: 41466

American (AMR) AF: 0.375 AC: 5731 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1369 AN: 3464

East Asian (EAS) AF: 0.478 AC: 2471 AN: 5166

South Asian (SAS) AF: 0.462 AC: 2219 AN: 4806

European-Finnish (FIN) AF: 0.446 AC: 4714 AN: 10560

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30353 AN: 67980

Other (OTH) AF: 0.413 AC: 873 AN: 2112

Alfa AF: 0.434 Hom.: 1844

Bravo AF: 0.425

Asia WGS AF: 0.444 AC: 1545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	15
DANN	Benign	0.26
PhyloP100		-0.017
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: rs6125646; hg19: chr20-48027409;