NM_004975.4:c.2572A>G

Variant names:

• chr20-49372988-T-C
• rs757668876
• NM_004975.4:c.2572A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_004975.4(KCNB1):​c.2572A>G​(p.Ile858Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000756 in 1,455,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.02
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17979088).
• BP6: Variant 20-49372988-T-C is Benign according to our data. Variant chr20-49372988-T-C is described in ClinVar as Benign. ClinVar VariationId is 2160995.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.2572A>G	p.Ile858Val	missense	Exon 2 of 2	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.2572A>G	p.Ile858Val	missense	Exon 2 of 2	ENSP00000360806.3	Q14721
	KCNB1	ENST00000635465.1	TSL:1	c.2572A>G	p.Ile858Val	missense	Exon 3 of 3	ENSP00000489193.1	Q14721
	KCNB1	ENST00000635878.1	TSL:5	c.97-73605A>G		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 244786 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000543

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1455348 Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5 AN XY: 723952

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 43866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5196

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109250

Other (OTH) AF: 0.0000167 AC: 1 AN: 60022

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 26 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.97	L
PhyloP100		4.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.090	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.048	D
Polyphen		0.20	B
Vest4		0.39
MutPred		0.31		Loss of glycosylation at S857 (P = 0.1703)
MVP		0.43
MPC		0.16
ClinPred		0.10	T
GERP RS		3.9
Varity_R		0.063
gMVP		0.35
Mutation Taster		=89/11	polymorphism

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: rs757668876; hg19: chr20-47989525;