chr11-67418903-G-C

Variant names:

• chr11-67418903-G-C
• rs750645891
• NM_001166222.2:c.512G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001166222.2(CARNS1):​c.512G>C​(p.Arg171Pro) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARNS1 NM_001166222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.920
• Publications: 2 publications found

Genes affected

CARNS1 (HGNC:29268): (carnosine synthase 1) CARNS1 (EC 6.3.2.11), a member of the ATP-grasp family of ATPases, catalyzes the formation of carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyryl-L-histidine), which are found mainly in skeletal muscle and the central nervous system, respectively (Drozak et al., 2010 [PubMed 20097752]).[supplied by OMIM, Apr 2010]

PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32813185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166222.2. 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
	CARNS1	NM_001166222.2	MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 5 of 10	NP_001159694.1	A5YM72-5
	CARNS1	NM_001394577.1		c.422G>C	p.Arg141Pro	missense	Exon 4 of 9	NP_001381506.1
	CARNS1	NM_001394578.1		c.143G>C	p.Arg48Pro	missense	Exon 4 of 9	NP_001381507.1	A5YM72-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNS1	ENST00000687366.1	MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 5 of 10	ENSP00000510668.1	A5YM72-5
	CARNS1	ENST00000307823.7	TSL:1	c.143G>C	p.Arg48Pro	missense	Exon 4 of 9	ENSP00000308268.3	A5YM72-1
	CARNS1	ENST00000445895.2	TSL:5	c.512G>C	p.Arg171Pro	missense	Exon 4 of 9	ENSP00000389009.2	A5YM72-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.92
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.59
MutPred		0.42		Loss of helix (P = 0.0237)
MVP		0.46
MPC		0.58
ClinPred		0.88	D
GERP RS		3.0
Varity_R		0.47
gMVP		0.71
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs750645891; hg19: chr11-67186374;