NM_001131.3:c.712T>G

Variant names:

• chr6-49835354-A-C
• rs768758510
• NM_001131.3:c.712T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001131.3(CRISP1):​c.712T>G​(p.Cys238Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C238S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CRISP1 NM_001131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

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.712T>G	p.Cys238Gly	missense	Exon 8 of 8	NP_001122.2
	CRISP1	NM_001205220.2		c.712T>G	p.Cys238Gly	missense	Exon 8 of 8	NP_001192149.1	P54107-1
	CRISP1	NM_170609.2		c.*86T>G		3_prime_UTR	Exon 7 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.712T>G	p.Cys238Gly	missense	Exon 8 of 8	ENSP00000338276.4	P54107-1
	CRISP1	ENST00000505118.1	TSL:1	c.712T>G	p.Cys238Gly	missense	Exon 8 of 8	ENSP00000427589.1	P54107-1
	CRISP1	ENST00000507853.5	TSL:1	c.*86T>G		3_prime_UTR	Exon 7 of 7	ENSP00000425020.1	P54107-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251294 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461532 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727080

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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	0.94
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0049	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		3.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.93		Loss of methylation at K239 (P = 0.016)
MVP		0.40
MPC		0.11
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.94
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768758510; hg19: chr6-49803067;