6-49846593-C-G

Variant names:

• chr6-49846593-C-G
• NM_001131.3:c.362G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001131.3(CRISP1):​c.362G>C​(p.Ser121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S121I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRISP1 NM_001131.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2777194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRISP1	NM_001131.3	c.362G>C	p.Ser121Thr	missense_variant	Exon 5 of 8	ENST00000335847.9	NP_001122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRISP1	ENST00000335847.9	c.362G>C	p.Ser121Thr	missense_variant	Exon 5 of 8	1	NM_001131.3	ENSP00000338276.4
CRISP1	ENST00000505118.1	c.362G>C	p.Ser121Thr	missense_variant	Exon 5 of 8	1		ENSP00000427589.1
CRISP1	ENST00000507853.5	c.362G>C	p.Ser121Thr	missense_variant	Exon 5 of 7	1		ENSP00000425020.1
CRISP1	ENST00000329411.9	c.362G>C	p.Ser121Thr	missense_variant	Exon 4 of 6	5		ENSP00000331317.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461318 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.10	.;T;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.60	.;.;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		0.40	B;P;B;P
Vest4		0.080
MutPred		0.46		Loss of disorder (P = 0.0784);Loss of disorder (P = 0.0784);Loss of disorder (P = 0.0784);Loss of disorder (P = 0.0784);
MVP		0.24
MPC		0.039
ClinPred		0.77	D
GERP RS		-0.15
Varity_R		0.12
gMVP		0.14

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: chr6-49814306;