2-69960757-C-G

Variant names:

• chr2-69960757-C-G
• rs373824162
• NM_152792.4:c.680G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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
• Publications: 0 publications found

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]

ASPRV1 Gene-Disease associations (from GenCC):

• ichthyosis, lamellar, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, G2P

ENSG00000293615 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 VariationId is 977279.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152792.4. 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
	ASPRV1	NM_152792.4	MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 1 of 1	NP_690005.3	Q53RT3-2
	ASPRV1	NR_170631.1		n.3223G>C		non_coding_transcript_exon	Exon 5 of 5
	ASPRV1	NR_170632.1		n.3373G>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPRV1	ENST00000320256.6	TSL:6 MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 1 of 1	ENSP00000315383.5	Q53RT3-2
	ENSG00000293615	ENST00000419542.6	TSL:5	c.932G>C	p.Arg311Pro	missense	Exon 6 of 6	ENSP00000520552.1
	ENSG00000293615	ENST00000630975.4	TSL:5	c.932G>C	p.Arg311Pro	missense	Exon 7 of 7	ENSP00000520555.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant lamellar ichthyosis (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
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
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs373824162; hg19: chr2-70187889;