5-79729290-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_153610.5(CMYA5):c.525G>T(p.Gln175His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,610,588 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: CMYA5 NM_153610.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.411

Genes affected

CMYA5 (HGNC:14305): (cardiomyopathy associated 5) Predicted to enable identical protein binding activity. Predicted to act upstream of or within negative regulation of calcineurin-NFAT signaling cascade; negative regulation of phosphoprotein phosphatase activity; and regulation of skeletal muscle adaptation. Located in cytosol; nuclear speck; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026955307).
• BP6: Variant 5-79729290-G-T is Benign according to our data. Variant chr5-79729290-G-T is described in ClinVar as [Benign]. Clinvar id is 733687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00615 (936/152268) while in subpopulation AFR AF= 0.0216 (898/41554). AF 95% confidence interval is 0.0204. There are 8 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMYA5	NM_153610.5	c.525G>T	p.Gln175His	missense_variant	2/13	ENST00000446378.3
CMYA5	XM_047416911.1	c.525G>T	p.Gln175His	missense_variant	2/6
CMYA5	XR_001742036.3	n.597G>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMYA5	ENST00000446378.3	c.525G>T	p.Gln175His	missense_variant	2/13	5	NM_153610.5	P1

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 936 AN: 152150 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00176 AC: 431 AN: 245068 Hom.: 2 AF XY: 0.00129 AC XY: 172 AN XY: 132906

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000634 AC: 924 AN: 1458320 Hom.: 9 Cov.: 34 AF XY: 0.000531 AC XY: 385 AN XY: 725410

Gnomad4 AFR exome AF: 0.0241

Gnomad4 AMR exome AF: 0.000935

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00615 AC: 936 AN: 152268 Hom.: 8 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74470

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00138 Hom.: 6

Bravo AF: 0.00698

ESP6500AA AF: 0.0232 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 267

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.86
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.060
Sift	Uncertain	0.010	D
Sift4G	Benign	0.14	T
Polyphen		0.94	P
Vest4		0.12
MutPred		0.11		Loss of sheet (P = 0.1158);
MVP		0.20
MPC		0.062
ClinPred		0.021	T
GERP RS		1.5
Varity_R		0.071
gMVP		0.22

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

Other links and lift over

dbSNP: rs6895605; hg19: chr5-79025113; COSMIC: COSV99069768;