Genetic Variant CFAP298:p.Val208Met (chr21-32603205-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021254.4(CFAP298):c.622G>A(p.Val208Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,212 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V208V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 53 hom. )

Consequence

CFAP298
NM_021254.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.57

Publications

7 publications found

Variant links:

Genes affected

CFAP298 (HGNC:1301): (cilia and flagella associated protein 298) This gene encodes a protein that plays a critical role in dynein arm assembly and motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Naturally occuring readthrough transcription occurs from this locus to the downstream t-complex 10 like (TCP10L) gene. [provided by RefSeq, Apr 2017]

CFAP298 links:

CFAP298-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

CFAP298-TCP10L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00909254).

BP6

Variant 21-32603205-C-T is Benign according to our data. Variant chr21-32603205-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00436 (664/152362) while in subpopulation NFE AF = 0.00678 (461/68040). AF 95% confidence interval is 0.00626. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFAP298	NM_021254.4	MANE Select	c.622G>A	p.Val208Met	missense	Exon 5 of 7	NP_067077.1
CFAP298-TCP10L	NM_001350338.2		c.622G>A	p.Val208Met	missense	Exon 5 of 8	NP_001337267.1
CFAP298	NM_001350337.2		c.622G>A	p.Val208Met	missense	Exon 5 of 6	NP_001337266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFAP298	ENST00000290155.8	TSL:1 MANE Select	c.622G>A	p.Val208Met	missense	Exon 5 of 7	ENSP00000290155.3
CFAP298-TCP10L	ENST00000673807.1		c.622G>A	p.Val208Met	missense	Exon 5 of 8	ENSP00000501088.1
CFAP298	ENST00000382549.8	TSL:1	c.622G>A	p.Val208Met	missense	Exon 5 of 5	ENSP00000371989.4

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

664

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00677

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00422

AC:

1062

AN:

251480

AF XY:

0.00444

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00430

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00607

AC:

8867

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4402

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.00248

AC:

111

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00659

AC:

568

AN:

86256

European-Finnish (FIN)

AF:

0.00453

AC:

242

AN:

53418

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00673

AC:

7488

AN:

1111976

Other (OTH)

AF:

0.00642

AC:

388

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

459

918

1376

1835

2294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00436

AC:

664

AN:

152362

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41580

American (AMR)

AF:

0.00379

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00461

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00678

AC:

461

AN:

68040

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00508

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00446

AC:

542

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Primary ciliary dyskinesia 26 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.020

MetaRNN

Benign

0.0091

MetaSVM

Uncertain

0.014

PhyloP100

2.6

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.55

MVP

0.16

MPC

0.51

ClinPred

0.013

GERP RS

5.4

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.41

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over