NM_001304964.2:c.458T>C

Variant names:

• chr12-75347659-T-C
• rs1462083846
• NM_001304964.2:c.458T>C

Variant summary

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

The NM_001304964.2(GLIPR1L1):​c.458T>C​(p.Val153Ala) 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 1,457,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLIPR1L1 NM_001304964.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.643
• Publications: 0 publications found

Genes affected

GLIPR1L1 (HGNC:28392): (GLIPR1 like 1) Predicted to be involved in single fertilization. Predicted to act upstream of or within binding activity of sperm to zona pellucida. Predicted to be located in sperm connecting piece. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

CAPS2 (HGNC:16471): (calcyphosine 2) Calcyphosine-2 is a calcium-binding protein with 2 EF-hand motifs (Wang et al., 2002 [PubMed 11846421]).[supplied by OMIM, Mar 2008]

CAPS2 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.2991557).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304964.2. 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
	GLIPR1L1	NM_001304964.2	MANE Select	c.458T>C	p.Val153Ala	missense	Exon 3 of 6	NP_001291893.1	Q6UWM5-1
	GLIPR1L1	NM_152779.4		c.458T>C	p.Val153Ala	missense	Exon 3 of 5	NP_689992.1	Q6UWM5-2
	CAPS2	NM_001355023.4		c.-29-21132A>G		intron	N/A	NP_001341952.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIPR1L1	ENST00000378695.9	TSL:1 MANE Select	c.458T>C	p.Val153Ala	missense	Exon 3 of 6	ENSP00000367967.4	Q6UWM5-1
	GLIPR1L1	ENST00000312442.2	TSL:1	c.458T>C	p.Val153Ala	missense	Exon 3 of 5	ENSP00000310770.2	Q6UWM5-2
	CAPS2	ENST00000328705.7	TSL:1	n.*372-22371A>G		intron	N/A	ENSP00000331007.3	H7BXT1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250552 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457778 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725244

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 85848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109392

Other (OTH) AF: 0.0000166 AC: 1 AN: 60182

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000578 AC: 2 AN: 3474

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	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.3
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.64
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.069
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.083	T
Polyphen		0.77	P
Vest4		0.19
MutPred		0.59		Gain of catalytic residue at V149 (P = 2e-04)
MVP		0.10
MPC		0.036
ClinPred		0.35	T
GERP RS		0.070
Varity_R		0.25
gMVP		0.66
Mutation Taster		=90/10	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: rs1462083846; hg19: chr12-75741439;