14-24507429-C-G

Variant names:

• chr14-24507429-C-G
• rs5246
• NM_001836.5:c.136G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001836.5(CMA1):​c.136G>C​(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,614,156 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (20 hom.)
• Consequence: CMA1 NM_001836.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.250
• Publications: 18 publications found

Genes affected

CMA1 (HGNC:2097): (chymase 1) This gene encodes a chymotryptic serine proteinase that belongs to the peptidase family S1. It is expressed in mast cells and is thought to function in the degradation of the extracellular matrix, the regulation of submucosal gland secretion, and the generation of vasoactive peptides. In the heart and blood vessels, this protein, rather than angiotensin converting enzyme, is largely responsible for converting angiotensin I to the vasoactive peptide angiotensin II. Alternative splicing results in multiple variants. [provided by RefSeq, Apr 2015]

ENSG00000258744 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063990355).
• BP6: Variant 14-24507429-C-G is Benign according to our data. Variant chr14-24507429-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 708801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001836.5. 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
	CMA1	NM_001836.5	MANE Select	c.136G>C	p.Gly46Arg	missense	Exon 2 of 5	NP_001827.1	P23946-1
	CMA1	NM_001308083.2		c.-125+749G>C		intron	N/A	NP_001295012.1	P23946-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMA1	ENST00000250378.7	TSL:1 MANE Select	c.136G>C	p.Gly46Arg	missense	Exon 2 of 5	ENSP00000250378.3	P23946-1
	CMA1	ENST00000206446.4	TSL:1	c.-125+749G>C		intron	N/A	ENSP00000206446.4	P23946-2
	ENSG00000258744	ENST00000555109.2	TSL:5	n.552-705C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00459 AC: 1154 AN: 251240 AF XY: 0.00478

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00411 AC: 6006 AN: 1461880 Hom.: 20 Cov.: 31 AF XY: 0.00424 AC XY: 3080 AN XY: 727240

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00306 AC: 137 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00849 AC: 222 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00323 AC: 279 AN: 86258

European-Finnish (FIN) AF: 0.0106 AC: 565 AN: 53420

Middle Eastern (MID) AF: 0.0160 AC: 92 AN: 5766

European-Non Finnish (NFE) AF: 0.00399 AC: 4439 AN: 1112002

Other (OTH) AF: 0.00402 AC: 243 AN: 60396

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74450

African (AFR) AF: 0.000866 AC: 36 AN: 41568

American (AMR) AF: 0.00242 AC: 37 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4818

European-Finnish (FIN) AF: 0.00867 AC: 92 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 68018

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00457 Hom.: 1

Bravo AF: 0.00342

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.25
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.28
MVP		0.75
MPC		0.0037
ClinPred		0.069	T
GERP RS		-1.2
Varity_R		0.45
gMVP		0.66
Mutation Taster		=98/2	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: rs5246; hg19: chr14-24976635;