chr1-110601790-A-G

Variant names:

• chr1-110601790-A-G
• rs201924903
• NM_004974.4:c.*1493T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004974.4(KCNA2):​c.*1493T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,139,810 control chromosomes in the GnomAD database, including 2,591 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (1082 hom., cov: 28)
  • Exomes 𝑓: 0.024 (1509 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.146
• Publications: 0 publications found

Genes affected

KCNA2 (HGNC:6220): (potassium voltage-gated channel subfamily A member 2) Potassium 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, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [provided by RefSeq, Jul 2008]

KCNA2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 32

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-110601790-A-G is Benign according to our data. Variant chr1-110601790-A-G is described in ClinVar as Benign. ClinVar VariationId is 1269688.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004974.4. 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
	KCNA2	NM_004974.4	MANE Select	c.*1493T>C		3_prime_UTR	Exon 3 of 3	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.1035+240T>C		intron	N/A	NP_001191198.1	P16389-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	ENST00000316361.10	TSL:2 MANE Select	c.*1493T>C		3_prime_UTR	Exon 3 of 3	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.1035+240T>C		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000633222.1	TSL:5	c.*1493T>C		3_prime_UTR	Exon 3 of 3	ENSP00000487785.1	P16389-1

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 13489 AN: 136590 Hom.: 1070 Cov.: 28

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.0566

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.0636

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0500

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0236 AC: 23650 AN: 1003134 Hom.: 1509 Cov.: 23 AF XY: 0.0242 AC XY: 11489 AN XY: 475262

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0224 AC: 469 AN: 20894

American (AMR) AF: 0.210 AC: 1476 AN: 7042

Ashkenazi Jewish (ASJ) AF: 0.0342 AC: 458 AN: 13398

East Asian (EAS) AF: 0.301 AC: 5493 AN: 18236

South Asian (SAS) AF: 0.0349 AC: 637 AN: 18236

European-Finnish (FIN) AF: 0.0744 AC: 1168 AN: 15702

Middle Eastern (MID) AF: 0.0239 AC: 64 AN: 2680

European-Non Finnish (NFE) AF: 0.0144 AC: 12485 AN: 867424

Other (OTH) AF: 0.0354 AC: 1400 AN: 39522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0988 AC: 13508 AN: 136676 Hom.: 1082 Cov.: 28 AF XY: 0.106 AC XY: 7025 AN XY: 66112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0758 AC: 2520 AN: 33252

American (AMR) AF: 0.256 AC: 3531 AN: 13788

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 215 AN: 3378

East Asian (EAS) AF: 0.356 AC: 1605 AN: 4508

South Asian (SAS) AF: 0.157 AC: 654 AN: 4174

European-Finnish (FIN) AF: 0.101 AC: 948 AN: 9354

Middle Eastern (MID) AF: 0.0500 AC: 14 AN: 280

European-Non Finnish (NFE) AF: 0.0578 AC: 3767 AN: 65150

Other (OTH) AF: 0.106 AC: 205 AN: 1926

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0820 Hom.: 24

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.64
PhyloP100		0.15
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: rs201924903; hg19: chr1-111144412;