10-68736923-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_018237.4(CCAR1):c.121A>G(p.Ile41Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CCAR1 NM_018237.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CCAR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.057215422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCAR1	NM_018237.4	c.121A>G	p.Ile41Val	missense_variant	3/25	ENST00000265872.11
CCAR1	NM_001282959.2	c.121A>G	p.Ile41Val	missense_variant	3/24
CCAR1	NM_001282960.2	c.121A>G	p.Ile41Val	missense_variant	3/24
CCAR1	NR_104262.2	n.221A>G		non_coding_transcript_exon_variant	3/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCAR1	ENST00000265872.11	c.121A>G	p.Ile41Val	missense_variant	3/25	1	NM_018237.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251334 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135828

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Aug 24, 2023

The c.121A>G (p.I41V) alteration is located in exon 3 (coding exon 2) of the CCAR1 gene. This alteration results from a A to G substitution at nucleotide position 121, causing the isoleucine (I) at amino acid position 41 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.025	T;.;T;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.60	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.46	N;.;N;N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.23	T;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.012, 0.0020	.;.;B;.;B;.;.
Vest4		0.24, 0.24, 0.23
MutPred		0.16		Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);Gain of phosphorylation at Y42 (P = 0.1095);
MVP		0.24
MPC		0.65
ClinPred		0.29	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.18

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: rs1383152823; hg19: chr10-70496680;