14-24507420-T-C

Variant names:

• chr14-24507420-T-C
• NM_001836.5:c.145A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001836.5(CMA1):​c.145A>G​(p.Lys49Glu) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CMA1 NM_001836.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -7.17

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

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=0.17012933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMA1	NM_001836.5	c.145A>G	p.Lys49Glu	missense_variant	Exon 2 of 5	ENST00000250378.7	NP_001827.1
CMA1	NM_001308083.2	c.-125+758A>G		intron_variant	Intron 1 of 3		NP_001295012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMA1	ENST00000250378.7	c.145A>G	p.Lys49Glu	missense_variant	Exon 2 of 5	1	NM_001836.5	ENSP00000250378.3
CMA1	ENST00000206446.4	c.-125+758A>G		intron_variant	Intron 1 of 3	1		ENSP00000206446.4
ENSG00000258744	ENST00000555109.1	n.144-714T>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145A>G (p.K49E) alteration is located in exon 2 (coding exon 2) of the CMA1 gene. This alteration results from a A to G substitution at nucleotide position 145, causing the lysine (K) at amino acid position 49 to be replaced by a glutamic acid (E). 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	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0010
DANN	Benign	0.26
DEOGEN2	Benign	0.25	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.089	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.68	T
Polyphen		0.012	B
Vest4		0.22
MutPred		0.62		Loss of methylation at K49 (P = 0.0014);
MVP		0.54
MPC		0.0023
ClinPred		0.14	T
GERP RS		-10
Varity_R		0.30
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24976626; COSMIC: COSV51626036;