chr2-134870969-G-T

Variant names:

• chr2-134870969-G-T
• NM_138326.3:c.585G>T

Variant summary

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

The NM_138326.3(ACMSD):​c.585G>T​(p.Met195Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACMSD NM_138326.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 0 publications found

Genes affected

ACMSD (HGNC:19288): (aminocarboxymuconate semialdehyde decarboxylase) The neuronal excitotoxin quinolinate is an intermediate in the de novo synthesis pathway of NAD from tryptophan, and has been implicated in the pathogenesis of several neurodegenerative disorders. Quinolinate is derived from alpha-amino-beta-carboxy-muconate-epsilon-semialdehyde (ACMS). ACMSD (ACMS decarboxylase; EC 4.1.1.45) can divert ACMS to a benign catabolite and thus prevent the accumulation of quinolinate from ACMS.[supplied by OMIM, Oct 2004]

CCNT2-AS1 (HGNC:40130): (CCNT2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138326.3. 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
	ACMSD	NM_138326.3	MANE Select	c.585G>T	p.Met195Ile	missense	Exon 7 of 10	NP_612199.2	Q8TDX5-1
	ACMSD	NM_001307983.2		c.411G>T	p.Met137Ile	missense	Exon 7 of 10	NP_001294912.1	A0A0S2Z681
	CCNT2-AS1	NR_036549.1		n.201-1928C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACMSD	ENST00000356140.10	TSL:1 MANE Select	c.585G>T	p.Met195Ile	missense	Exon 7 of 10	ENSP00000348459.5	Q8TDX5-1
	ACMSD	ENST00000392928.5	TSL:1	c.411G>T	p.Met137Ile	missense	Exon 7 of 10	ENSP00000376659.1	Q8TDX5-2
	ACMSD	ENST00000904289.1		c.630G>T	p.Met210Ile	missense	Exon 8 of 11	ENSP00000574348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.54
MutPred		0.68		Loss of phosphorylation at T200 (P = 0.1713)
MVP		0.54
MPC		0.26
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.92
Mutation Taster		=24/76	disease causing

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

hg19: chr2-135628539;