NM_004588.5:c.625_626delAAinsCC

Variant names:

• chr11-118166909-TT-GG
• rs1064796044
• NM_004588.5:c.625_626delAAinsCC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_004588.5(SCN2B):​c.625_626delAAinsCC​(p.Asn209Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2B NM_004588.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.85

Genes affected

SCN2B (HGNC:10589): (sodium voltage-gated channel beta subunit 2) The protein encoded by this gene is the beta 2 subunit of the type II voltage-gated sodium channel. The encoded protein is involved in cell-cell adhesion and cell migration. Defects in this gene can be a cause of Brugada Syndrome, atrial fibrillation, or sudden infant death syndrome. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-118166909-TT-GG is Benign according to our data. Variant chr11-118166909-TT-GG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422854.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2B	NM_004588.5	c.625_626delAAinsCC	p.Asn209Pro	missense_variant		ENST00000278947.6	NP_004579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2B	ENST00000278947.6	c.625_626delAAinsCC	p.Asn209Pro	missense_variant		1	NM_004588.5	ENSP00000278947.5
SCN2B	ENST00000658882.1	n.*450_*451delAAinsCC		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000499572.1
SCN2B	ENST00000669850.1	n.867_868delAAinsCC		non_coding_transcript_exon_variant	Exon 4 of 4
SCN2B	ENST00000658882.1	n.*450_*451delAAinsCC		3_prime_UTR_variant	Exon 5 of 5			ENSP00000499572.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Atrial fibrillation, familial, 14 Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 209 of the SCN2B protein (p.Asn209Pro). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with epilepsy (PMID: 10976944). ClinVar contains an entry for this variant (Variation ID: 422854). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Apr 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with juvenile myoclonic epilepsy (JME), but did not segregate with disease in an affected sibling (Haug et al., 2000); In silico analysis supports that this variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 10976944) -

Cardiovascular phenotype Benign:1

Nov 14, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064796044; hg19: chr11-118037624;