NM_148674.5:c.2562+7A>G

Variant names:

• chr22-45362878-T-C
• rs719925
• NM_148674.5:c.2562+7A>G

Variant summary

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

The NM_148674.5(SMC1B):​c.2562+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,576,770 control chromosomes in the GnomAD database, including 194,532 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (13747 hom., cov: 32)
  • Exomes 𝑓: 0.50 (180785 hom.)
• Consequence: SMC1B NM_148674.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002911
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.261
• Publications: 34 publications found

Genes affected

SMC1B (HGNC:11112): (structural maintenance of chromosomes 1B) SMC1L2 belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis (3:Revenkova et al., 2001 [PubMed 11564881]).[supplied by OMIM, Mar 2008]

SMC1B Gene-Disease associations (from GenCC):

• gonadal dysgenesis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1B	NM_148674.5	c.2562+7A>G		splice_region_variant, intron_variant	Intron 16 of 24	ENST00000357450.9	NP_683515.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1B	ENST00000357450.9	c.2562+7A>G		splice_region_variant, intron_variant	Intron 16 of 24	5	NM_148674.5	ENSP00000350036.4
SMC1B	ENST00000404354.3	c.2562+7A>G		splice_region_variant, intron_variant	Intron 16 of 22	1		ENSP00000385902.3

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59399 AN: 151968 Hom.: 13745 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.439 AC: 98656 AN: 224848 AF XY: 0.439

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.469

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.495 AC: 705528 AN: 1424686 Hom.: 180785 Cov.: 29 AF XY: 0.493 AC XY: 349430 AN XY: 709446

African (AFR) AF: 0.125 AC: 3990 AN: 31844

American (AMR) AF: 0.462 AC: 17116 AN: 37050

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 11889 AN: 25388

East Asian (EAS) AF: 0.368 AC: 14373 AN: 39030

South Asian (SAS) AF: 0.341 AC: 27450 AN: 80458

European-Finnish (FIN) AF: 0.473 AC: 25111 AN: 53040

Middle Eastern (MID) AF: 0.388 AC: 2208 AN: 5696

European-Non Finnish (NFE) AF: 0.528 AC: 576601 AN: 1093080

Other (OTH) AF: 0.453 AC: 26790 AN: 59100

GnomAD4 genome AF: 0.391 AC: 59410 AN: 152084 Hom.: 13747 Cov.: 32 AF XY: 0.386 AC XY: 28668 AN XY: 74322

African (AFR) AF: 0.144 AC: 5965 AN: 41526

American (AMR) AF: 0.432 AC: 6599 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1631 AN: 3466

East Asian (EAS) AF: 0.317 AC: 1637 AN: 5162

South Asian (SAS) AF: 0.323 AC: 1557 AN: 4826

European-Finnish (FIN) AF: 0.457 AC: 4819 AN: 10550

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35838 AN: 67968

Other (OTH) AF: 0.399 AC: 842 AN: 2112

Alfa AF: 0.481 Hom.: 36260

Bravo AF: 0.379

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.8
DANN	Benign	0.71
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs719925; hg19: chr22-45758758; COSMIC: COSV62529860;