22-45359924-T-C

Position:

• chr22-45359924-T-C

Variant summary

Our verdict is Likely benign. Variant got -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. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1B	NM_148674.5	c.2743A>G	p.Ile915Val	missense_variant	18/25	ENST00000357450.9	NP_683515.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1B	ENST00000357450.9	c.2743A>G	p.Ile915Val	missense_variant	18/25	5	NM_148674.5	ENSP00000350036.4
SMC1B	ENST00000404354.3	c.2743A>G	p.Ile915Val	missense_variant	18/23	1		ENSP00000385902.3

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.2743A>G (p.I915V) alteration is located in exon 18 (coding exon 18) of the SMC1B gene. This alteration results from a A to G substitution at nucleotide position 2743, causing the isoleucine (I) at amino acid position 915 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.11
Sift	Benign	0.29	T;T
Sift4G	Benign	0.82	T;T
Vest4		0.30
MutPred		0.40		Gain of ubiquitination at K910 (P = 0.0817);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs989797617; hg19: chr22-45755804;