rs7008482

Variant names:

• chr8-125255388-T-G
• rs7008482
• NM_173685.4:c.418+73132T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173685.4(NSMCE2):​c.418+73132T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 152,066 control chromosomes in the GnomAD database, including 21,661 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (21661 hom., cov: 32)
• Consequence: NSMCE2 NM_173685.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• Publications: 30 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMCE2	NM_173685.4	c.418+73132T>G		intron_variant	Intron 5 of 7	ENST00000287437.8	NP_775956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMCE2	ENST00000287437.8	c.418+73132T>G		intron_variant	Intron 5 of 7	1	NM_173685.4	ENSP00000287437.3
NSMCE2	ENST00000522563.6	c.418+73132T>G		intron_variant	Intron 4 of 6	5		ENSP00000430668.1
NSMCE2	ENST00000517532.5	c.418+73132T>G		intron_variant	Intron 5 of 6	5		ENSP00000429612.1
NSMCE2	ENST00000517315.1	c.238+73132T>G		intron_variant	Intron 4 of 6	3		ENSP00000428846.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72302 AN: 151946 Hom.: 21597 Cov.: 32

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.476 AC: 72417 AN: 152066 Hom.: 21661 Cov.: 32 AF XY: 0.479 AC XY: 35580 AN XY: 74338

African (AFR) AF: 0.851 AC: 35289 AN: 41480

American (AMR) AF: 0.371 AC: 5671 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1294 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2186 AN: 5176

South Asian (SAS) AF: 0.578 AC: 2777 AN: 4806

European-Finnish (FIN) AF: 0.304 AC: 3215 AN: 10584

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20757 AN: 67962

Other (OTH) AF: 0.446 AC: 941 AN: 2112

Alfa AF: 0.370 Hom.: 41717

Bravo AF: 0.491

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.33
PhyloP100		0.22
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: rs7008482; hg19: chr8-126267630;