20-49373020-C-G

Variant names:

• chr20-49373020-C-G
• rs769688446
• NM_004975.4:c.2540G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004975.4(KCNB1):​c.2540G>C​(p.Gly847Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G847V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17191523).
• BP6: Variant 20-49373020-C-G is Benign according to our data. Variant chr20-49373020-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2866807.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2540G>C	p.Gly847Ala	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.2540G>C	p.Gly847Ala	missense	Exon 2 of 2	ENSP00000360806.3	Q14721
	KCNB1	ENST00000635465.1	TSL:1	c.2540G>C	p.Gly847Ala	missense	Exon 3 of 3	ENSP00000489193.1	Q14721
	KCNB1	ENST00000635878.1	TSL:5	c.97-73637G>C		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250644 AF XY: 0.00000738

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461254 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111708

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	0.078
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.32
Sift	Benign	0.037	D
Sift4G	Benign	0.26	T
Polyphen		0.13	B
Vest4		0.14
MutPred		0.38		Loss of disorder (P = 0.0973)
MVP		0.22
MPC		0.22
ClinPred		0.051	T
GERP RS		4.1
Varity_R		0.065
gMVP		0.64
Mutation Taster		=95/5	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: rs769688446; hg19: chr20-47989557;