16-85100147-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198491.3(CIBAR2):​c.745G>A​(p.Ala249Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,608,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CIBAR2 NM_198491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046572357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIBAR2	NM_198491.3	c.745G>A	p.Ala249Thr	missense_variant	Exon 8 of 9	ENST00000539556.6	NP_940893.1
CIBAR2	NM_001366920.1	c.745G>A	p.Ala249Thr	missense_variant	Exon 8 of 9		NP_001353849.1
CIBAR2	XM_011523063.2	c.745G>A	p.Ala249Thr	missense_variant	Exon 8 of 10		XP_011521365.1
CIBAR2	XM_017023198.2	c.745G>A	p.Ala249Thr	missense_variant	Exon 8 of 10		XP_016878687.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIBAR2	ENST00000539556.6	c.745G>A	p.Ala249Thr	missense_variant	Exon 8 of 9	5	NM_198491.3	ENSP00000443411.1
CIBAR2	ENST00000618669.3	c.460G>A	p.Ala154Thr	missense_variant	Exon 6 of 7	5		ENSP00000478373.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245140 AF XY: 0.00000754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1456788 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5 AN XY: 724356

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

American (AMR) AF: 0.0000228 AC: 1 AN: 43790

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

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39554

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84748

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53366

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

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109840

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000555

EpiControl AF: 0.000120

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.745G>A (p.A249T) alteration is located in exon 8 (coding exon 8) of the FAM92B gene. This alteration results from a G to A substitution at nucleotide position 745, causing the alanine (A) at amino acid position 249 to be replaced by a threonine (T). 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	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.23
DANN	Benign	0.85
DEOGEN2	Benign	0.00085	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N
PhyloP100		-1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.27	N;.
REVEL	Benign	0.014
Sift	Benign	0.55	T;.
Sift4G	Benign	0.38	T;T
Polyphen		0.022	.;B
Vest4		0.12
MutPred		0.12		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.061
MPC		0.034
ClinPred		0.029	T
GERP RS		-3.2
Varity_R		0.034
gMVP		0.061
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs759998712; hg19: chr16-85133753;