1-16929897-A-G

Position:

• chr1-16929897-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014675.5(CROCC):​c.403A>G​(p.Arg135Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,435,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 47)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CROCC NM_014675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.425

Genes affected

CROCC (HGNC:21299): (ciliary rootlet coiled-coil, rootletin) Predicted to enable kinesin binding activity and structural molecule activity. Involved in several processes, including centriole-centriole cohesion; positive regulation of cilium assembly; and positive regulation of protein localization to cilium. Located in cytoskeleton; cytosol; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CROCC (HGNC:):

ACMG classification

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=0.08272508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CROCC	NM_014675.5	c.403A>G	p.Arg135Gly	missense_variant	4/37	ENST00000375541.10	NP_055490.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CROCC	ENST00000375541.10	c.403A>G	p.Arg135Gly	missense_variant	4/37	5	NM_014675.5	ENSP00000364691.4
CROCC	ENST00000467938.5	c.82A>G	p.Arg28Gly	missense_variant	2/17	2		ENSP00000480016.1
CROCC	ENST00000445545.6	c.199-389A>G		intron_variant		5		ENSP00000402626.2
CROCC	ENST00000466256.6	n.126-389A>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 47

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1435412 Hom.: 0 Cov.: 35 AF XY: 0.00000562 AC XY: 4 AN XY: 712220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0000364

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 47

ExAC AF: 0.0000167 AC: 2

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

Sep 26, 2024

The c.403A>G (p.R135G) alteration is located in exon 4 (coding exon 4) of the CROCC gene. This alteration results from a A to G substitution at nucleotide position 403, causing the arginine (R) at amino acid position 135 to be replaced by a glycine (G). 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	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.090
Sift	Benign	0.032	D
Sift4G	Uncertain	0.025	D
Vest4		0.15
MutPred		0.24		Gain of helix (P = 0.0022);
MVP		0.18
MPC		0.064
ClinPred		0.038	T
GERP RS		-2.7
gMVP		0.072

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

Other links and lift over

dbSNP: rs777106541; hg19: chr1-17256392;