chr20-4724975-C-G

Variant names:

• chr20-4724975-C-G
• rs1372243155
• NM_012409.4:c.424C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012409.4(PRND):​c.424C>G​(p.Leu142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. L142F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRND NM_012409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 0 publications found

Genes affected

PRND (HGNC:15748): (prion like protein doppel) This gene is found on chromosome 20, approximately 20 kbp downstream of the gene encoding cellular prion protein, to which it is biochemically and structurally similar. The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that is found predominantly in testis. Mutations in this gene may lead to neurological disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025447518).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012409.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRND	NM_012409.4	MANE Select	c.424C>G	p.Leu142Val	missense	Exon 2 of 2	NP_036541.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRND	ENST00000305817.3	TSL:1 MANE Select	c.424C>G	p.Leu142Val	missense	Exon 2 of 2	ENSP00000306900.2	Q9UKY0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0080
DANN	Benign	0.13
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-1.6
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.17
Sift	Benign	0.89	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.056
MutPred		0.34		Gain of methylation at K143 (P = 0.0423)
MVP		0.27
MPC		0.089
ClinPred		0.035	T
GERP RS		-3.3
Varity_R		0.031
gMVP		0.31
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1372243155; hg19: chr20-4705621;