10-68754793-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_018237.4(CCAR1):c.1424G>A(p.Arg475Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,455,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CCAR1 NM_018237.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

Genes affected

CCAR1 (HGNC:24236): (cell division cycle and apoptosis regulator 1) Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; nuclear receptor coactivator activity; and transcription corepressor activity. Involved in positive regulation of cell migration and positive regulation of cell population proliferation. Acts upstream of or within positive regulation of apoptotic process. Located in nuclear envelope lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CCAR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2221309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCAR1	NM_018237.4	c.1424G>A	p.Arg475Gln	missense_variant	12/25	ENST00000265872.11
CCAR1	NM_001282959.2	c.1379G>A	p.Arg460Gln	missense_variant	11/24
CCAR1	NM_001282960.2	c.1379G>A	p.Arg460Gln	missense_variant	11/24
CCAR1	NR_104262.2	n.1524G>A		non_coding_transcript_exon_variant	12/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCAR1	ENST00000265872.11	c.1424G>A	p.Arg475Gln	missense_variant	12/25	1	NM_018237.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251296 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1455954 Hom.: 0 Cov.: 27 AF XY: 0.0000138 AC XY: 10 AN XY: 724738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Apr 28, 2022

The c.1424G>A (p.R475Q) alteration is located in exon 12 (coding exon 11) of the CCAR1 gene. This alteration results from a G to A substitution at nucleotide position 1424, causing the arginine (R) at amino acid position 475 to be replaced by a glutamine (Q). 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	0.24
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Uncertain	0.056	T;D;D;D;D;T
Polyphen		0.98, 0.88, 0.86	.;D;P;.;P;.
Vest4		0.27
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0999);Gain of relative solvent accessibility (P = 0.0999);.;.;.;.;
MVP		0.38
MPC		0.91
ClinPred		0.33	T
GERP RS		6.0
Varity_R		0.14
gMVP		0.39

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: rs923596775; hg19: chr10-70514550; COSMIC: COSV56274980; COSMIC: COSV56274980;