chr5-79729172-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153610.5(CMYA5):​c.407A>T​(p.His136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CMYA5
NM_153610.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.162
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.048074633).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CMYA5NM_153610.5 linkuse as main transcriptc.407A>T p.His136Leu missense_variant 2/13 ENST00000446378.3 NP_705838.3
CMYA5XM_047416911.1 linkuse as main transcriptc.407A>T p.His136Leu missense_variant 2/6 XP_047272867.1
CMYA5XR_001742036.3 linkuse as main transcriptn.479A>T non_coding_transcript_exon_variant 2/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CMYA5ENST00000446378.3 linkuse as main transcriptc.407A>T p.His136Leu missense_variant 2/135 NM_153610.5 ENSP00000394770 P1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152232
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
247906
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134426
show subpopulations
Gnomad AFR exome
AF:
0.000194
Gnomad AMR exome
AF:
0.0000292
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460510
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
726432
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.000539
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 19, 2022The c.407A>T (p.H136L) alteration is located in exon 2 (coding exon 2) of the CMYA5 gene. This alteration results from a A to T substitution at nucleotide position 407, causing the histidine (H) at amino acid position 136 to be replaced by a leucine (L). 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
0.12
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
1.3
DANN
Benign
0.92
DEOGEN2
Benign
0.027
T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.47
T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.048
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-3.2
D
REVEL
Benign
0.041
Sift
Benign
0.13
T
Sift4G
Benign
0.45
T
Polyphen
0.45
P
Vest4
0.19
MVP
0.25
MPC
0.066
ClinPred
0.035
T
GERP RS
0.85
Varity_R
0.11
gMVP
0.094

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: rs371922369; hg19: chr5-79024995; API