9-75016275-C-G

Variant names:

• chr9-75016275-C-G
• NM_152420.3:c.583G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_152420.3(CARNMT1):​c.583G>C​(p.Glu195Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E195G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARNMT1 NM_152420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

Genes affected

CARNMT1 (HGNC:23435): (carnosine N-methyltransferase 1) The protein encoded by this gene is a methyltransferase that converts carnosine to anserine, a dipeptide found abundantly in skeletal muscle. The encoded protein can methylate other dipeptides as well. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ENSG00000229587 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.8756 (below the threshold of 3.09). Trascript score misZ: 0.3004 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.165957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152420.3. 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
	CARNMT1	NM_152420.3	MANE Select	c.583G>C	p.Glu195Gln	missense	Exon 3 of 8	NP_689633.1	Q8N4J0
	CARNMT1	NM_001320497.2		c.346G>C	p.Glu116Gln	missense	Exon 3 of 8	NP_001307426.1
	CARNMT1	NR_135282.1		n.772G>C		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNMT1	ENST00000376834.8	TSL:1 MANE Select	c.583G>C	p.Glu195Gln	missense	Exon 3 of 8	ENSP00000366030.3	Q8N4J0
	CARNMT1	ENST00000928755.1		c.583G>C	p.Glu195Gln	missense	Exon 3 of 9	ENSP00000598814.1
	CARNMT1	ENST00000956154.1		c.583G>C	p.Glu195Gln	missense	Exon 3 of 8	ENSP00000626213.1

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	Benign	0.14
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
PhyloP100		5.7
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.031
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.085	B
Vest4		0.24
MutPred		0.42		Loss of ubiquitination at K190 (P = 0.0373)
MVP		0.043
MPC		0.34
ClinPred		0.86	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.70
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr9-77631191;