Genetic Variant NSMCE2:p.Ala234GlufsTer4 (chr8-125366837-A-AAGGG) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_173685.4(NSMCE2):c.697_700dupAGGG(p.Ala234GlufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NSMCE2
NM_173685.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.01

Publications

0 publications found

Variant links:

Genes affected

NSMCE2 (HGNC:26513): (NSE2 (MMS21) homolog, SMC5-SMC6 complex SUMO ligase) This gene encodes a member of a family of E3 small ubiquitin-related modifier (SUMO) ligases that mediates the attachment of a SUMO protein to proteins involved in nuclear transport, transcription, chromosome segregation and DNA repair. The encoded protein is part of the structural maintenance of chromosomes (SMC) 5/6 complex which plays a key role genome maintenance, facilitating chromosome segregation and suppressing mitotic recombination. A knockout of the orthologous mouse gene is lethal prior to embryonic day 10.5. Naturally occurring mutations in this gene, that abolish the SUMO ligase activity, are associated with primordial dwarfism and extreme insulin resistance. [provided by RefSeq, Mar 2017]

NSMCE2 Gene-Disease associations (from GenCC):

Seckel syndrome 10
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
microcephalic primordial dwarfism-insulin resistance syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NSMCE2 links:

ENSG00000254431 (HGNC:):

ENSG00000254431 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0578 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-125366837-A-AAGGG is Pathogenic according to our data. Variant chr8-125366837-A-AAGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 372286.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMCE2	NM_173685.4 link	c.697_700dupAGGG	p.Ala234GlufsTer4	frameshift_variant	Exon 8 of 8	ENST00000287437.8	NP_775956.1	Q96MF7A0A024R9J6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMCE2	ENST00000287437.8 link	c.697_700dupAGGG	p.Ala234GlufsTer4	frameshift_variant	Exon 8 of 8	1	NM_173685.4	ENSP00000287437.3		Q96MF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111490

Other (OTH)

AF:

0.0000166

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Seckel syndrome 10

Pathogenic:1

Dec 15, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over