6-49846659-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001131.3(CRISP1):​c.296G>A​(p.Cys99Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C99S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CRISP1
NM_001131.3 missense

Scores

4
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRISP1NM_001131.3 linkc.296G>A p.Cys99Tyr missense_variant Exon 5 of 8 ENST00000335847.9 NP_001122.2 P54107-1A0A0K0K1I1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CRISP1ENST00000335847.9 linkc.296G>A p.Cys99Tyr missense_variant Exon 5 of 8 1 NM_001131.3 ENSP00000338276.4 P54107-1
CRISP1ENST00000505118.1 linkc.296G>A p.Cys99Tyr missense_variant Exon 5 of 8 1 ENSP00000427589.1 P54107-1
CRISP1ENST00000507853.5 linkc.296G>A p.Cys99Tyr missense_variant Exon 5 of 7 1 ENSP00000425020.1 P54107-2
CRISP1ENST00000329411.9 linkc.296G>A p.Cys99Tyr missense_variant Exon 4 of 6 5 ENSP00000331317.5 P54107-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
.;T;.;T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.78
.;.;T;T
M_CAP
Benign
0.0078
T
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.5
L;L;L;L
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-11
D;D;D;D
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.81
MutPred
0.60
Gain of phosphorylation at C99 (P = 0.0349);Gain of phosphorylation at C99 (P = 0.0349);Gain of phosphorylation at C99 (P = 0.0349);Gain of phosphorylation at C99 (P = 0.0349);
MVP
0.48
MPC
0.11
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.92
gMVP
0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-49814372; API