chr2-134871006-A-G

Position:

• chr2-134871006-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000356140.10(ACMSD):​c.622A>G​(p.Met208Val) 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 ENST00000356140.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACMSD	NM_138326.3	c.622A>G	p.Met208Val	missense_variant	7/10	ENST00000356140.10	NP_612199.2
CCNT2-AS1	NR_036549.1	n.201-1965T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACMSD	ENST00000356140.10	c.622A>G	p.Met208Val	missense_variant	7/10	1	NM_138326.3	ENSP00000348459	P1
CCNT2-AS1	ENST00000392929.6	n.109-1965T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 22, 2023

The c.622A>G (p.M208V) alteration is located in exon 7 (coding exon 7) of the ACMSD gene. This alteration results from a A to G substitution at nucleotide position 622, causing the methionine (M) at amino acid position 208 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	Benign	0.31
BayesDel_addAF	Benign	0.0087	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0045	T
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.050	T;T
Polyphen		0.057	B;.
Vest4		0.70
MutPred		0.70		Gain of catalytic residue at M208 (P = 0.0177);.;
MVP		0.30
MPC		0.13
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.53
gMVP		0.89

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: chr2-135628576;