6-49840917-C-G

Variant names:

• chr6-49840917-C-G
• rs372119257
• NM_001131.3:c.514G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001131.3(CRISP1):​c.514G>C​(p.Val172Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V172I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRISP1 NM_001131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.72
• Publications: 1 publications found

Genes affected

CRISP1 (HGNC:304): (cysteine rich secretory protein 1) Fertilization consists of a sequence of specific cell-cell interactions culminating in the fusion of the sperm and egg plasma membranes. Recognition, binding, and fusion occur through the interaction of complementary molecules that are localized to specific domains of the sperm and egg plasma membranes. In the sperm, the postacrosomal region or equatorial segment is involved in sperm-egg plasma membrane fusion. The protein encoded by this gene is a member of the cysteine-rich secretory protein (CRISP) family. It is expressed in the epididymis, is secreted into the epididymal lumen, and binds to the postacrosomal region of the sperm head, where it plays a role in sperm-egg fusion. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3260172).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131.3. 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
	CRISP1	NM_001131.3	MANE Select	c.514G>C	p.Val172Leu	missense	Exon 6 of 8	NP_001122.2
	CRISP1	NM_001205220.2		c.514G>C	p.Val172Leu	missense	Exon 6 of 8	NP_001192149.1	P54107-1
	CRISP1	NM_170609.2		c.514G>C	p.Val172Leu	missense	Exon 6 of 7	NP_733758.1	P54107-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRISP1	ENST00000335847.9	TSL:1 MANE Select	c.514G>C	p.Val172Leu	missense	Exon 6 of 8	ENSP00000338276.4	P54107-1
	CRISP1	ENST00000505118.1	TSL:1	c.514G>C	p.Val172Leu	missense	Exon 6 of 8	ENSP00000427589.1	P54107-1
	CRISP1	ENST00000507853.5	TSL:1	c.514G>C	p.Val172Leu	missense	Exon 6 of 7	ENSP00000425020.1	P54107-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250948 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461084 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726858

⚠️ 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: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111528

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		-1.7
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.021	D
Polyphen		0.58	P
Vest4		0.44
MutPred		0.61		Gain of catalytic residue at V172 (P = 0.1179)
MVP		0.18
MPC		0.075
ClinPred		0.93	D
GERP RS		-5.1
Varity_R		0.23
gMVP		0.50
Mutation Taster		=94/6	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: rs372119257; hg19: chr6-49808630;