5-65563375-C-G

Variant names:

• chr5-65563375-C-G
• rs762283295
• NM_015342.4:c.65C>G

Variant summary

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

The NM_015342.4(PPWD1):​c.65C>G​(p.Pro22Arg) 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. 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. P22L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPWD1 NM_015342.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

PPWD1 (HGNC:28954): (peptidylprolyl isomerase domain and WD repeat containing 1) Enables cyclosporin A binding activity and peptidyl-prolyl cis-trans isomerase activity. Involved in protein peptidyl-prolyl isomerization. Located in nuclear body. Part of catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

CENPK (HGNC:29479): (centromere protein K) CENPK is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 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=0.058347136).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015342.4. 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
	PPWD1	NM_015342.4	MANE Select	c.65C>G	p.Pro22Arg	missense	Exon 1 of 11	NP_056157.1	Q96BP3-1
	PPWD1	NM_001278926.2		c.-63C>G		5_prime_UTR	Exon 1 of 12	NP_001265855.1	F5H7P7
	PPWD1	NM_001278927.2		c.-183C>G		5_prime_UTR	Exon 1 of 11	NP_001265856.1	B4DP34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPWD1	ENST00000261308.10	TSL:1 MANE Select	c.65C>G	p.Pro22Arg	missense	Exon 1 of 11	ENSP00000261308.4	Q96BP3-1
	PPWD1	ENST00000902252.1		c.65C>G	p.Pro22Arg	missense	Exon 1 of 11	ENSP00000572311.1
	PPWD1	ENST00000942942.1		c.65C>G	p.Pro22Arg	missense	Exon 1 of 9	ENSP00000613001.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.066
Sift	Benign	0.12	T
Sift4G	Benign	0.46	T
Polyphen		0.013	B
Vest4		0.17
MVP		0.56
MPC		0.29
ClinPred		0.085	T
GERP RS		3.1
PromoterAI		-0.11	Neutral
Varity_R		0.034
gMVP		0.32
Mutation Taster		=92/8	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: rs762283295; hg19: chr5-64859202;