8-22613118-C-G

Variant names:

• chr8-22613118-C-G
• rs1317710585
• NM_001393997.1:c.686C>G

Variant summary

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

The NM_001393997.1(CCAR2):​c.686C>G​(p.Thr229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CCAR2 NM_001393997.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

Genes affected

CCAR2 (HGNC:23360): (cell cycle and apoptosis regulator 2) Enables RNA polymerase II complex binding activity and enzyme inhibitor activity. Involved in several processes, including regulation of cellular protein metabolic process; regulation of signal transduction; and regulation of transcription, DNA-templated. Located in several cellular components, including mitochondrial matrix; nucleoplasm; and spindle. Part of DBIRD complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.20162892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCAR2	NM_001393997.1	c.686C>G	p.Thr229Ser	missense_variant	Exon 8 of 21	ENST00000308511.9	NP_001380926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCAR2	ENST00000308511.9	c.686C>G	p.Thr229Ser	missense_variant	Exon 8 of 21	1	NM_001393997.1	ENSP00000310670.4
CCAR2	ENST00000389279.7	c.686C>G	p.Thr229Ser	missense_variant	Exon 8 of 21	1		ENSP00000373930.3
CCAR2	ENST00000520861	c.-290C>G		5_prime_UTR_variant	Exon 4 of 16	1		ENSP00000429773.1
CCAR2	ENST00000522599.5	c.140C>G	p.Thr47Ser	missense_variant	Exon 1 of 5	5		ENSP00000429739.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686C>G (p.T229S) alteration is located in exon 8 (coding exon 7) of the CCAR2 gene. This alteration results from a C to G substitution at nucleotide position 686, causing the threonine (T) at amino acid position 229 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.069	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.92	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.93	P;P;.
Vest4		0.35
MutPred		0.34		Gain of disorder (P = 0.0646);Gain of disorder (P = 0.0646);.;
MVP		0.32
MPC		0.11
ClinPred		0.71	D
GERP RS		5.9
Varity_R		0.067
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1317710585; hg19: chr8-22470631;