20-49469732-T-C

Variant names:

• chr20-49469732-T-C
• rs802952
• NM_004975.4:c.567+12182A>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.567+12182A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,334 control chromosomes in the GnomAD database, including 11,678 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 0.38 (11678 hom., cov: 29)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 7 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.567+12182A>G		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.567+12182A>G		intron_variant	Intron 2 of 2		XP_011527101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.567+12182A>G		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.567+12182A>G		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+12182A>G		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
KCNB1	ENST00000636950.1	n.87+12182A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.384 AC: 57998 AN: 151218 Hom.: 11673 Cov.: 29

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.383 AC: 58010 AN: 151334 Hom.: 11678 Cov.: 29 AF XY: 0.377 AC XY: 27844 AN XY: 73900

African (AFR) AF: 0.345 AC: 14205 AN: 41172

American (AMR) AF: 0.325 AC: 4953 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3468

East Asian (EAS) AF: 0.190 AC: 980 AN: 5154

South Asian (SAS) AF: 0.316 AC: 1519 AN: 4802

European-Finnish (FIN) AF: 0.338 AC: 3486 AN: 10304

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.443 AC: 30038 AN: 67882

Other (OTH) AF: 0.425 AC: 896 AN: 2108

Alfa AF: 0.420 Hom.: 10953

Bravo AF: 0.381

Asia WGS AF: 0.272 AC: 943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.21
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: rs802952; hg19: chr20-48086269;