1-16924438-C-T

Position:

• chr1-16924438-C-T

Variant summary

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

The NM_014675.5(CROCC):​c.310C>T​(p.Arg104Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 52)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CROCC NM_014675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CROCC	NM_014675.5	c.310C>T	p.Arg104Cys	missense_variant	3/37	ENST00000375541.10	NP_055490.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CROCC	ENST00000375541.10	c.310C>T	p.Arg104Cys	missense_variant	3/37	5	NM_014675.5	ENSP00000364691.4
CROCC	ENST00000445545.6	c.157C>T	p.Arg53Cys	missense_variant	2/24	5		ENSP00000402626.2
CROCC	ENST00000467938.5	c.30+1640C>T		intron_variant		2		ENSP00000480016.1
CROCC	ENST00000466256.6	n.126-5848C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 52

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460990 Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 8 AN XY: 726806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 52

Alfa AF: 0.0000936 Hom.: 0

ExAC AF: 0.0000247 AC: 3

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

Oct 29, 2024

The c.310C>T (p.R104C) alteration is located in exon 3 (coding exon 3) of the CROCC gene. This alteration results from a C to T substitution at nucleotide position 310, causing the arginine (R) at amino acid position 104 to be replaced by a cysteine (C). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.65
MutPred		0.51		Loss of MoRF binding (P = 0.0614);
MVP		0.30
MPC		0.33
ClinPred		0.92	D
GERP RS		4.0
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200540396; hg19: chr1-17250933; COSMIC: COSV65010877;