NM_001166222.2:c.511C>A

Variant names:

• chr11-67418902-C-A
• rs781336685
• NM_001166222.2:c.511C>A

Variant summary

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

The NM_001166222.2(CARNS1):​c.511C>A​(p.Arg171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CARNS1 NM_001166222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.918

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

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 rank	MANE	Protein	UniProt
CARNS1	NM_001166222.2	c.511C>A	p.Arg171Ser	missense_variant	Exon 5 of 10	ENST00000687366.1	NP_001159694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARNS1	ENST00000687366.1	c.511C>A	p.Arg171Ser	missense_variant	Exon 5 of 10		NM_001166222.2	ENSP00000510668.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1442546 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.68	.;P;.
Vest4		0.33
MutPred		0.41		.;Gain of catalytic residue at R48 (P = 0.0101);.;
MVP		0.47
MPC		0.32
ClinPred		0.64	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781336685; hg19: chr11-67186373;