22-45359924-T-C

Variant names:

• chr22-45359924-T-C
• rs989797617
• NM_148674.5:c.2743A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_148674.5(SMC1B):​c.2743A>G​(p.Ile915Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SMC1B NM_148674.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0240
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.095808774).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.2743A>G	p.Ile915Val	missense	Exon 18 of 25	NP_683515.4
	SMC1B	NM_001291501.2		c.2743A>G	p.Ile915Val	missense	Exon 18 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.2743A>G	p.Ile915Val	missense	Exon 18 of 25	ENSP00000350036.4	Q8NDV3-3
	SMC1B	ENST00000404354.3	TSL:1	c.2743A>G	p.Ile915Val	missense	Exon 18 of 23	ENSP00000385902.3	Q8NDV3-2
	SMC1B	ENST00000877413.1		c.2767A>G	p.Ile923Val	missense	Exon 18 of 23	ENSP00000547472.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726994

African (AFR) AF: 0.000239 AC: 8 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.10
DANN	Benign	0.29
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.024
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.11
Sift	Benign	0.29	T
Sift4G	Benign	0.82	T
Vest4		0.30
MutPred		0.40		Gain of ubiquitination at K910 (P = 0.0817)
MVP		0.45
MPC		0.23
ClinPred		0.19	T
GERP RS		-0.99
gMVP		0.078
Mutation Taster		=96/4	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: rs989797617; hg19: chr22-45755804;