12-121923805-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144668.6(CFAP251):c.562C>T(p.Arg188Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,614,014 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (55 hom.)
• Consequence: CFAP251 NM_144668.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00900

Genes affected

CFAP251 (HGNC:28506): (cilia and flagella associated protein 251) This protein encoded by this gene belongs to the WD repeat-containing family of proteins, which function in the formation of protein-protein complexes in a variety of biological pathways. This family member appears to function in the determination of mean platelet volume (MPV), and polymorphisms in this gene have been associated with variance in MPV. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034005642).
• BP6: Variant 12-121923805-C-T is Benign according to our data. Variant chr12-121923805-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2643490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP251	NM_144668.6	c.562C>T	p.Arg188Trp	missense_variant	3/22	ENST00000288912.9
CFAP251	NM_001178003.2	c.562C>T	p.Arg188Trp	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP251	ENST00000288912.9	c.562C>T	p.Arg188Trp	missense_variant	3/22	1	NM_144668.6
CFAP251	ENST00000397454.2	c.562C>T	p.Arg188Trp	missense_variant	3/18	1		P1
CFAP251	ENST00000540779.1	n.460C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00508 AC: 772 AN: 152004 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00912

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00479 AC: 1196 AN: 249558 Hom.: 5 AF XY: 0.00475 AC XY: 643 AN XY: 135392

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00808 AC: 11811 AN: 1461892 Hom.: 55 Cov.: 31 AF XY: 0.00776 AC XY: 5644 AN XY: 727246

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00292

Gnomad4 NFE exome AF: 0.00978

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152122 Hom.: 2 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74376

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00912

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00782 Hom.: 11

Bravo AF: 0.00494

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00214 AC: 8

ESP6500EA AF: 0.00830 AC: 68

ExAC AF: 0.00473 AC: 571

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00563

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CFAP251-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

CFAP251: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	13
Dann	Benign	0.60
DEOGEN2	Benign	0.0068	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.057
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.0010	B;.
Vest4		0.040
MVP		0.13
MPC		0.13
ClinPred		0.011	T
GERP RS		2.5
Varity_R		0.039
gMVP		0.14

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: rs34703321; hg19: chr12-122361711; COSMIC: COSV99062164; COSMIC: COSV99062164;