NM_001142286.2:c.1312A>T

Variant names:

• chr2-17716775-T-A
• rs534834201
• NM_001142286.2:c.1312A>T

Variant summary

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

The NM_001142286.2(SMC6):​c.1312A>T​(p.Ile438Leu) 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. 16/22 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. I438V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMC6 NM_001142286.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849
• Publications: 1 publications found

Genes affected

SMC6 (HGNC:20466): (structural maintenance of chromosomes 6) Enables ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; positive regulation of chromosome segregation; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.10668966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142286.2. 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
	SMC6	NM_001142286.2	MANE Select	c.1312A>T	p.Ile438Leu	missense	Exon 14 of 28	NP_001135758.1	Q96SB8-1
	SMC6	NM_024624.6		c.1312A>T	p.Ile438Leu	missense	Exon 13 of 27	NP_078900.1	A0A2S1ZR87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC6	ENST00000448223.7	TSL:1 MANE Select	c.1312A>T	p.Ile438Leu	missense	Exon 14 of 28	ENSP00000404092.2	Q96SB8-1
	SMC6	ENST00000351948.8	TSL:1	c.1312A>T	p.Ile438Leu	missense	Exon 13 of 27	ENSP00000323439.4	Q96SB8-1
	SMC6	ENST00000446852.5	TSL:1	c.1390A>T	p.Ile464Leu	missense	Exon 15 of 20	ENSP00000408644.1	C9JMN1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.85
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.055
Sift	Benign	0.14	T
Sift4G	Benign	0.51	T
Polyphen		0.014	B
Vest4		0.31
MutPred		0.48		Gain of ubiquitination at K442 (P = 0.2763)
MVP		0.29
MPC		0.29
ClinPred		0.39	T
GERP RS		3.4
Varity_R		0.093
gMVP		0.31
Mutation Taster		=82/18	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: rs534834201; hg19: chr2-17898042;