8-74986193-A-C

Variant names:

• chr8-74986193-A-C
• rs1812493085
• NM_031461.6:c.206A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031461.6(CRISPLD1):​c.206A>C​(p.His69Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. H69R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRISPLD1 NM_031461.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.73
• Publications: 0 publications found

Genes affected

CRISPLD1 (HGNC:18206): (cysteine rich secretory protein LCCL domain containing 1) Involved in face morphogenesis. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031461.6. 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
	CRISPLD1	NM_031461.6	MANE Select	c.206A>C	p.His69Pro	missense	Exon 2 of 15	NP_113649.1	Q9H336-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRISPLD1	ENST00000262207.9	TSL:1 MANE Select	c.206A>C	p.His69Pro	missense	Exon 2 of 15	ENSP00000262207.4	Q9H336-1
	CRISPLD1	ENST00000959492.1		c.206A>C	p.His69Pro	missense	Exon 2 of 15	ENSP00000629551.1
	CRISPLD1	ENST00000916000.1		c.206A>C	p.His69Pro	missense	Exon 2 of 15	ENSP00000586059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Pathogenic	4.9	H
PhyloP100		8.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.78		Gain of ubiquitination at K71 (P = 0.0851)
MVP		0.83
MPC		0.97
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.98
Mutation Taster		=5/95	disease causing

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: rs1812493085; hg19: chr8-75898428;