14-105479046-C-G

Variant names:

• chr14-105479046-C-G
• rs781981653
• NM_001312.4:c.405C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001312.4(CRIP2):​c.405C>G​(p.Phe135Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRIP2 NM_001312.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005377
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.84
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001312.4. 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
	CRIP2	NM_001312.4	MANE Select	c.405C>G	p.Phe135Leu	missense splice_region	Exon 5 of 8	NP_001303.1	P52943-1
	CRIP2	NM_001270837.2		c.627C>G	p.Phe209Leu	missense splice_region	Exon 5 of 8	NP_001257766.1	P52943-2
	CRIP2	NM_001270841.2		c.44-79C>G		intron	N/A	NP_001257770.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRIP2	ENST00000329146.9	TSL:1 MANE Select	c.405C>G	p.Phe135Leu	missense splice_region	Exon 5 of 8	ENSP00000328521.5	P52943-1
	CRIP2	ENST00000548309.1	TSL:1	n.1200C>G		splice_region non_coding_transcript_exon	Exon 5 of 8
	CRIP2	ENST00000483017.7	TSL:2	c.627C>G	p.Phe209Leu	missense splice_region	Exon 5 of 8	ENSP00000426119.2	P52943-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422644 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 704212

African (AFR) AF: 0.00 AC: 0 AN: 32726

American (AMR) AF: 0.00 AC: 0 AN: 39736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 37832

South Asian (SAS) AF: 0.00 AC: 0 AN: 81374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4158

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094184

Other (OTH) AF: 0.00 AC: 0 AN: 58810

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	2.2
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.089	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.96	L
PhyloP100		-2.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.50
Sift	Benign	0.10	T
Sift4G	Benign	0.064	T
Polyphen		0.99	D
Vest4		0.71
MutPred		0.45		Gain of catalytic residue at K131 (P = 0.0211)
MVP		0.88
MPC		0.55
ClinPred		0.97	D
GERP RS		-0.64
Varity_R		0.19
gMVP		0.57
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.040		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: rs781981653; hg19: chr14-105945383;