16-85100147-C-G

Variant names:

• chr16-85100147-C-G
• rs759998712
• NM_198491.3:c.745G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198491.3(CIBAR2):​c.745G>C​(p.Ala249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A249T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CIBAR2 NM_198491.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 0 publications found

Genes affected

CIBAR2 (HGNC:24781): (CBY1 interacting BAR domain containing 2) Predicted to be involved in cilium assembly. Predicted to be located in centriole and cytoplasm. Predicted to be active in ciliary basal body and ciliary transition zone. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12335399).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198491.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIBAR2	NM_198491.3	MANE Select	c.745G>C	p.Ala249Pro	missense	Exon 8 of 9	NP_940893.1	A0A1X7SC74
	CIBAR2	NM_001366920.1		c.745G>C	p.Ala249Pro	missense	Exon 8 of 9	NP_001353849.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIBAR2	ENST00000539556.6	TSL:5 MANE Select	c.745G>C	p.Ala249Pro	missense	Exon 8 of 9	ENSP00000443411.1	A0A1X7SC74
	CIBAR2	ENST00000618669.3	TSL:5	c.460G>C	p.Ala154Pro	missense	Exon 6 of 7	ENSP00000478373.1	A0A087WU51

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456788 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724356

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 43790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109840

Other (OTH) AF: 0.00 AC: 0 AN: 60228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000555

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.067
Sift	Benign	0.10	T
Sift4G	Uncertain	0.037	D
Polyphen		0.93	P
Vest4		0.17
MutPred		0.27		Loss of helix (P = 0.0068)
MVP		0.12
MPC		0.041
ClinPred		0.25	T
GERP RS		-3.2
Varity_R		0.085
gMVP		0.14

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

Other links and lift over

dbSNP: rs759998712; hg19: chr16-85133753;