rs2452600

Variant names:

• chr4-94575731-C-T
• rs2452600
• NM_006457.5:c.407C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006457.5(PDLIM5):​c.407C>T​(p.Ser136Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,613,468 control chromosomes in the GnomAD database, including 72,280 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S136A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5347 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66933 hom.)
• Consequence: PDLIM5 NM_006457.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• Publications: 57 publications found

Genes affected

PDLIM5 (HGNC:17468): (PDZ and LIM domain 5) This gene encodes a member of a family of proteins that possess a 100-amino acid PDZ domain at the N terminus and one to three LIM domains at the C-terminus. This family member functions as a scaffold protein that tethers protein kinases to the Z-disk in striated muscles. It is thought to function in cardiomyocyte expansion and in restraining postsynaptic growth of excitatory synapses. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017850399).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM5	NM_006457.5	c.407C>T	p.Ser136Phe	missense_variant	Exon 5 of 13	ENST00000317968.9	NP_006448.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM5	ENST00000317968.9	c.407C>T	p.Ser136Phe	missense_variant	Exon 5 of 13	1	NM_006457.5	ENSP00000321746.4

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38294 AN: 151910 Hom.: 5345 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.266 AC: 66966 AN: 251338 AF XY: 0.264

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.297 AC: 433815 AN: 1461440 Hom.: 66933 Cov.: 36 AF XY: 0.293 AC XY: 212727 AN XY: 727040

African (AFR) AF: 0.129 AC: 4314 AN: 33476

American (AMR) AF: 0.247 AC: 11032 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7776 AN: 26132

East Asian (EAS) AF: 0.423 AC: 16794 AN: 39698

South Asian (SAS) AF: 0.140 AC: 12108 AN: 86244

European-Finnish (FIN) AF: 0.275 AC: 14709 AN: 53410

Middle Eastern (MID) AF: 0.239 AC: 1378 AN: 5768

European-Non Finnish (NFE) AF: 0.314 AC: 349060 AN: 1111606

Other (OTH) AF: 0.276 AC: 16644 AN: 60386

GnomAD4 genome AF: 0.252 AC: 38297 AN: 152028 Hom.: 5347 Cov.: 32 AF XY: 0.251 AC XY: 18654 AN XY: 74308

African (AFR) AF: 0.132 AC: 5470 AN: 41462

American (AMR) AF: 0.266 AC: 4066 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1011 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1951 AN: 5154

South Asian (SAS) AF: 0.133 AC: 640 AN: 4824

European-Finnish (FIN) AF: 0.279 AC: 2947 AN: 10556

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21356 AN: 67968

Other (OTH) AF: 0.274 AC: 578 AN: 2110

Alfa AF: 0.295 Hom.: 34294

Bravo AF: 0.247

TwinsUK AF: 0.328 AC: 1215

ALSPAC AF: 0.319 AC: 1229

ESP6500AA AF: 0.135 AC: 594

ESP6500EA AF: 0.310 AC: 2668

ExAC AF: 0.262 AC: 31794

Asia WGS AF: 0.213 AC: 742 AN: 3478

EpiCase AF: 0.309

EpiControl AF: 0.305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		2.4
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.076
Sift	Uncertain	0.024	D;.
Sift4G	Uncertain	0.029	D;D
Polyphen		0.93	P;.
Vest4		0.11
ClinPred		0.020	T
GERP RS		4.4
Varity_R		0.20
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2452600; hg19: chr4-95496882; COSMIC: COSV58749958; COSMIC: COSV58749958;