6-49846546-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001131.3(CRISP1):​c.409G>C​(p.Asp137His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CRISP1
NM_001131.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07935396).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRISP1NM_001131.3 linkc.409G>C p.Asp137His 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.409G>C p.Asp137His missense_variant Exon 5 of 8 1 NM_001131.3 ENSP00000338276.4 P54107-1
CRISP1ENST00000505118.1 linkc.409G>C p.Asp137His missense_variant Exon 5 of 8 1 ENSP00000427589.1 P54107-1
CRISP1ENST00000507853.5 linkc.409G>C p.Asp137His missense_variant Exon 5 of 7 1 ENSP00000425020.1 P54107-2
CRISP1ENST00000329411.9 linkc.409G>C p.Asp137His missense_variant Exon 4 of 6 5 ENSP00000331317.5 P54107-2

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250904
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135590
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000871
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1461172
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726880
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000896
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000117
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.409G>C (p.D137H) alteration is located in exon 5 (coding exon 4) of the CRISP1 gene. This alteration results from a G to C substitution at nucleotide position 409, causing the aspartic acid (D) at amino acid position 137 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.13
.;T;.;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.62
.;.;T;T
M_CAP
Benign
0.0025
T
MetaRNN
Benign
0.079
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.6
M;M;M;M
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.3
N;N;N;N
REVEL
Benign
0.056
Sift
Benign
0.13
T;T;T;T
Sift4G
Benign
0.16
T;T;T;T
Polyphen
0.73
P;P;P;P
Vest4
0.12
MVP
0.35
MPC
0.053
ClinPred
0.066
T
GERP RS
1.4
Varity_R
0.052
gMVP
0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150800115; hg19: chr6-49814259; API