9-75017313-T-C

Variant names:

• chr9-75017313-T-C
• NM_152420.3:c.366A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152420.3(CARNMT1):​c.366A>G​(p.Ile122Met) 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. 12/18 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. I122V) 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: 0.0200

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23657525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARNMT1	NM_152420.3	c.366A>G	p.Ile122Met	missense_variant	Exon 2 of 8	ENST00000376834.8	NP_689633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARNMT1	ENST00000376834.8	c.366A>G	p.Ile122Met	missense_variant	Exon 2 of 8	1	NM_152420.3	ENSP00000366030.3
CARNMT1	ENST00000376830.3	c.366A>G	p.Ile122Met	missense_variant	Exon 2 of 2	1		ENSP00000366026.3
CARNMT1	ENST00000451153.1	c.183A>G	p.Ile61Met	missense_variant	Exon 2 of 5	3		ENSP00000396353.1

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

May 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.366A>G (p.I122M) alteration is located in exon 2 (coding exon 2) of the CARNMT1 gene. This alteration results from a A to G substitution at nucleotide position 366, causing the isoleucine (I) at amino acid position 122 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.96	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.032	D;.;D
Polyphen		0.0070	B;.;.
Vest4		0.42
MutPred		0.61		Gain of catalytic residue at I122 (P = 0.1063);.;Gain of catalytic residue at I122 (P = 0.1063);
MVP		0.10
MPC		0.18
ClinPred		0.83	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.55

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: chr9-77632229;