chr22-45344560-C-G

Variant names:

• chr22-45344560-C-G
• rs757744760
• NM_148674.5:c.3704G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_148674.5(SMC1B):​c.3704G>C​(p.Arg1235Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1235H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMC1B NM_148674.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.47
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0732182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148674.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1B	NM_148674.5	MANE Select	c.3704G>C	p.Arg1235Pro	missense	Exon 25 of 25	NP_683515.4
	SMC1B	NM_001291501.2		c.3482G>C	p.Arg1161Pro	missense	Exon 23 of 23	NP_001278430.1	Q8NDV3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1B	ENST00000357450.9	TSL:5 MANE Select	c.3704G>C	p.Arg1235Pro	missense	Exon 25 of 25	ENSP00000350036.4	Q8NDV3-3
	SMC1B	ENST00000404354.3	TSL:1	c.3482G>C	p.Arg1161Pro	missense	Exon 23 of 23	ENSP00000385902.3	Q8NDV3-2
	SMC1B	ENST00000877413.1		c.3506G>C	p.Arg1169Pro	missense	Exon 23 of 23	ENSP00000547472.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.14
DANN	Benign	0.66
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.96	T
PhyloP100		-3.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MutPred		0.23		Gain of glycosylation at R1235 (P = 0.0635)
MVP		0.33
MPC		0.83
ClinPred		0.52	D
GERP RS		-11
gMVP		0.32
Mutation Taster		=92/8	polymorphism

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: rs757744760; hg19: chr22-45740441;