11-67418529-A-G

Variant names:

• chr11-67418529-A-G
• rs1790733
• NM_001166222.2:c.364+9A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001166222.2(CARNS1):​c.364+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,526,254 control chromosomes in the GnomAD database, including 29,160 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (12144 hom., cov: 33)
  • Exomes 𝑓: 0.10 (17016 hom.)
• Consequence: CARNS1 NM_001166222.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.529
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNS1	NM_001166222.2	MANE Select	c.364+9A>G		intron	N/A	NP_001159694.1
	CARNS1	NM_001394577.1		c.275-227A>G		intron	N/A	NP_001381506.1
	CARNS1	NM_001394578.1		c.-6+9A>G		intron	N/A	NP_001381507.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNS1	ENST00000687366.1	MANE Select	c.364+9A>G		intron	N/A	ENSP00000510668.1
	CARNS1	ENST00000307823.7	TSL:1	c.-6+9A>G		intron	N/A	ENSP00000308268.3
	CARNS1	ENST00000445895.2	TSL:5	c.364+9A>G		intron	N/A	ENSP00000389009.2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43363 AN: 151898 Hom.: 12099 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.183 AC: 24841 AN: 135928 AF XY: 0.157

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.0587

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0724

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.102 AC: 140472 AN: 1374236 Hom.: 17016 Cov.: 31 AF XY: 0.0980 AC XY: 66348 AN XY: 677254

African (AFR) AF: 0.738 AC: 22882 AN: 31022

American (AMR) AF: 0.418 AC: 14181 AN: 33946

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 1537 AN: 24826

East Asian (EAS) AF: 0.250 AC: 8839 AN: 35306

South Asian (SAS) AF: 0.0646 AC: 5072 AN: 78526

European-Finnish (FIN) AF: 0.120 AC: 4163 AN: 34696

Middle Eastern (MID) AF: 0.101 AC: 573 AN: 5646

European-Non Finnish (NFE) AF: 0.0705 AC: 75629 AN: 1072920

Other (OTH) AF: 0.132 AC: 7596 AN: 57348

GnomAD4 genome AF: 0.286 AC: 43471 AN: 152018 Hom.: 12144 Cov.: 33 AF XY: 0.283 AC XY: 21023 AN XY: 74292

African (AFR) AF: 0.715 AC: 29650 AN: 41462

American (AMR) AF: 0.317 AC: 4841 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1304 AN: 5152

South Asian (SAS) AF: 0.0682 AC: 329 AN: 4824

European-Finnish (FIN) AF: 0.125 AC: 1322 AN: 10584

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0774 AC: 5255 AN: 67934

Other (OTH) AF: 0.229 AC: 481 AN: 2104

Alfa AF: 0.122 Hom.: 1543

Bravo AF: 0.326

Asia WGS AF: 0.226 AC: 785 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs1790733; hg19: chr11-67186000; COSMIC: COSV57130945; COSMIC: COSV57130945;