9-104100118-C-T

Variant names:

• chr9-104100118-C-T
• NM_006444.3:c.506C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006444.3(SMC2):​c.506C>T​(p.Ala169Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMC2 NM_006444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81

Genes affected

SMC2 (HGNC:14011): (structural maintenance of chromosomes 2) Predicted to enable ATP binding activity; chromatin binding activity; and single-stranded DNA binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytoplasm; and nuclear lumen. Part of condensin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC2	NM_006444.3	c.506C>T	p.Ala169Val	missense_variant	Exon 6 of 25	ENST00000374793.8	NP_006435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC2	ENST00000374793.8	c.506C>T	p.Ala169Val	missense_variant	Exon 6 of 25	1	NM_006444.3	ENSP00000363925.3
SMC2	ENST00000286398.11	c.506C>T	p.Ala169Val	missense_variant	Exon 6 of 25	1		ENSP00000286398.7
SMC2	ENST00000374787.7	c.506C>T	p.Ala169Val	missense_variant	Exon 6 of 25	2		ENSP00000363919.3
SMC2	ENST00000440179.5	c.71C>T	p.Ala24Val	missense_variant	Exon 4 of 6	3		ENSP00000414999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424738 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 708732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.506C>T (p.A169V) alteration is located in exon 6 (coding exon 5) of the SMC2 gene. This alteration results from a C to T substitution at nucleotide position 506, causing the alanine (A) at amino acid position 169 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
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;T;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H;.;H;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.86
MutPred		0.75		Loss of disorder (P = 0.0617);.;Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);
MVP		0.58
MPC		0.56
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-106862399;