2-69960757-C-G

Position:

• chr2-69960757-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_152792.4(ASPRV1):​c.680G>C​(p.Arg227Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ASPRV1 NM_152792.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.61

Genes affected

ASPRV1 (HGNC:26321): (aspartic peptidase retroviral like 1) Filaggrin is a structural protein that is crucial for in the development and maintenance of the skin barrier. This gene encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. Expression is found primarily in the epidermis and inner root sheath of hair follicles. [provided by RefSeq, May 2017]

PCBP1-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Retroviral-like aspartic protease 1 (size 135) in uniprot entity APRV1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_152792.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-69960757-C-G is Pathogenic according to our data. Variant chr2-69960757-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 977279.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-69960757-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPRV1	NM_152792.4	c.680G>C	p.Arg227Pro	missense_variant	1/1	ENST00000320256.6	NP_690005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPRV1	ENST00000320256.6	c.680G>C	p.Arg227Pro	missense_variant	1/1	6	NM_152792.4	ENSP00000315383.5
PCBP1-AS1	ENST00000682294.1	n.4106G>C		non_coding_transcript_exon_variant	8/8			ENSP00000520553.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant lamellar ichthyosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.43		Loss of sheet (P = 0.0228);
MVP		0.67
MPC		0.58
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.70

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: rs373824162; hg19: chr2-70187889;