8-125151151-G-A

Variant names:

• chr8-125151151-G-A
• NM_173685.4:c.158-20G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_173685.4(NSMCE2):​c.158-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000084 in 1,189,812 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: NSMCE2 NM_173685.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.797
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-125151151-G-A is Benign according to our data. Variant chr8-125151151-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2975558.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMCE2	NM_173685.4	c.158-20G>A		intron_variant	Intron 3 of 7	ENST00000287437.8	NP_775956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMCE2	ENST00000287437.8	c.158-20G>A		intron_variant	Intron 3 of 7	1	NM_173685.4	ENSP00000287437.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.40e-7 AC: 1 AN: 1189812 Hom.: 0 Cov.: 15 AF XY: 0.00000166 AC XY: 1 AN XY: 602624

African (AFR) AF: 0.00 AC: 0 AN: 28134

American (AMR) AF: 0.00 AC: 0 AN: 42800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23814

East Asian (EAS) AF: 0.00 AC: 0 AN: 37840

South Asian (SAS) AF: 0.00 AC: 0 AN: 77388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5064

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 872596

Other (OTH) AF: 0.00 AC: 0 AN: 50886

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.33
PhyloP100		-0.80

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

hg19: chr8-126163393;