9-74984913-C-G

Variant names:

• chr9-74984913-C-G
• rs758086570
• NM_152420.3:c.1122G>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.1122G>C​(p.Lys374Asn) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 0.167
• 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]

CARNMT1-AS1 (HGNC:51188): (CARNMT1 antisense RNA 1)

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=0.10942006).

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.1122G>C	p.Lys374Asn	missense	Exon 7 of 8	NP_689633.1	Q8N4J0
	CARNMT1	NM_001320497.2		c.885G>C	p.Lys295Asn	missense	Exon 7 of 8	NP_001307426.1
	CARNMT1	NR_135282.1		n.1170G>C		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNMT1	ENST00000376834.8	TSL:1 MANE Select	c.1122G>C	p.Lys374Asn	missense	Exon 7 of 8	ENSP00000366030.3	Q8N4J0
	CARNMT1-AS1	ENST00000455609.2	TSL:1	n.249-6252C>G		intron	N/A
	CARNMT1	ENST00000928755.1		c.1197G>C	p.Lys399Asn	missense	Exon 8 of 9	ENSP00000598814.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.17
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.024
Sift	Benign	0.41	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.29
MutPred		0.48		Loss of methylation at K374 (P = 0.0075)
MVP		0.043
MPC		1.5
ClinPred		0.27	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.72
Mutation Taster		=78/22	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: rs758086570; hg19: chr9-77599829;