14-105479214-G-A

Position:

• chr14-105479214-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001312.4(CRIP2):​c.496G>A​(p.Ala166Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,084 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CRIP2 NM_001312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

CRIP2 (HGNC:2361): (cysteine rich protein 2) This gene encodes a putative transcription factor with two LIM zinc-binding domains. The encoded protein may participate in the differentiation of smooth muscle tissue. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

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, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRIP2	NM_001312.4	c.496G>A	p.Ala166Thr	missense_variant	6/8	ENST00000329146.9	NP_001303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRIP2	ENST00000329146.9	c.496G>A	p.Ala166Thr	missense_variant	6/8	1	NM_001312.4	ENSP00000328521	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458084 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 725260

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The c.496G>A (p.A166T) alteration is located in exon 6 (coding exon 6) of the CRIP2 gene. This alteration results from a G to A substitution at nucleotide position 496, causing the alanine (A) at amino acid position 166 to be replaced by a threonine (T). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.0	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Pathogenic	0.65
Sift	Benign	0.17	T;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	.;D
Vest4		0.71
MutPred		0.52		.;Gain of catalytic residue at E167 (P = 0.0015);
MVP		0.93
MPC		0.86
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.56

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: chr14-105945551;