14-24505599-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001836.5(CMA1):​c.661C>T​(p.Arg221Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CMA1
NM_001836.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.766
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2197192).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CMA1NM_001836.5 linkc.661C>T p.Arg221Trp missense_variant Exon 5 of 5 ENST00000250378.7 NP_001827.1 P23946-1Q4FEB3
CMA1NM_001308083.2 linkc.328C>T p.Arg110Trp missense_variant Exon 4 of 4 NP_001295012.1 P23946-2Q4FEB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CMA1ENST00000250378.7 linkc.661C>T p.Arg221Trp missense_variant Exon 5 of 5 1 NM_001836.5 ENSP00000250378.3 P23946-1
CMA1ENST00000206446.4 linkc.328C>T p.Arg110Trp missense_variant Exon 4 of 4 1 ENSP00000206446.4 P23946-2
ENSG00000258744ENST00000555109.1 linkn.144-2535G>A intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
250900
Hom.:
0
AF XY:
0.0000590
AC XY:
8
AN XY:
135566
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000810
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461740
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000738
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.661C>T (p.R221W) alteration is located in exon 5 (coding exon 5) of the CMA1 gene. This alteration results from a C to T substitution at nucleotide position 661, causing the arginine (R) at amino acid position 221 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.56
D;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.036
N
LIST_S2
Benign
0.69
T;D
M_CAP
Uncertain
0.092
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
0.92
L;.
PrimateAI
Benign
0.25
T
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Benign
0.29
Sift
Uncertain
0.026
D;D
Sift4G
Benign
0.17
T;T
Polyphen
1.0
D;.
Vest4
0.28
MVP
0.95
MPC
0.0083
ClinPred
0.30
T
GERP RS
1.0
Varity_R
0.53
gMVP
0.55

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755977857; hg19: chr14-24974805; COSMIC: COSV51625626; API