10-68753884-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_018237.4(CCAR1):c.1151G>A(p.Arg384His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,628 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: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CCAR1 NM_018237.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

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 Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CCAR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCAR1	NM_018237.4	c.1151G>A	p.Arg384His	missense_variant	11/25	ENST00000265872.11
CCAR1	NM_001282959.2	c.1106G>A	p.Arg369His	missense_variant	10/24
CCAR1	NM_001282960.2	c.1106G>A	p.Arg369His	missense_variant	10/24
CCAR1	NR_104262.2	n.1251G>A		non_coding_transcript_exon_variant	11/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCAR1	ENST00000265872.11	c.1151G>A	p.Arg384His	missense_variant	11/25	1	NM_018237.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251348 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461628 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

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

Jul 13, 2021

The c.1151G>A (p.R384H) alteration is located in exon 11 (coding exon 10) of the CCAR1 gene. This alteration results from a G to A substitution at nucleotide position 1151, causing the arginine (R) at amino acid position 384 to be replaced by a histidine (H). 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	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D;.
Vest4		0.92
MVP		0.81
MPC		2.0
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1320054408; hg19: chr10-70513641;