NM_021254.4:c.77A>C

Variant names:

• chr21-32612167-T-G
• rs138178722
• NM_021254.4:c.77A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021254.4(CFAP298):​c.77A>C​(p.Glu26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,597,998 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (17 hom.)
• Consequence: CFAP298 NM_021254.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.42
• Publications: 4 publications found

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-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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008645952).
• BP6: Variant 21-32612167-T-G is Benign according to our data. Variant chr21-32612167-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00233 (355/152264) while in subpopulation AMR AF = 0.00908 (139/15304). AF 95% confidence interval is 0.00785. There are 2 homozygotes in GnomAd4. There are 176 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP298	NM_021254.4	MANE Select	c.77A>C	p.Glu26Ala	missense	Exon 1 of 7	NP_067077.1
	CFAP298-TCP10L	NM_001350338.2		c.77A>C	p.Glu26Ala	missense	Exon 1 of 8	NP_001337267.1
	CFAP298	NM_001350337.2		c.77A>C	p.Glu26Ala	missense	Exon 1 of 6	NP_001337266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP298	ENST00000290155.8	TSL:1 MANE Select	c.77A>C	p.Glu26Ala	missense	Exon 1 of 7	ENSP00000290155.3
	CFAP298-TCP10L	ENST00000673807.1		c.77A>C	p.Glu26Ala	missense	Exon 1 of 8	ENSP00000501088.1
	CFAP298	ENST00000382549.8	TSL:1	c.77A>C	p.Glu26Ala	missense	Exon 1 of 5	ENSP00000371989.4

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00252 AC: 551 AN: 218886 AF XY: 0.00259

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.00760

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00601

GnomAD4 exome AF: 0.00181 AC: 2618 AN: 1445734 Hom.: 17 Cov.: 31 AF XY: 0.00192 AC XY: 1376 AN XY: 717476

African (AFR) AF: 0.00114 AC: 38 AN: 33244

American (AMR) AF: 0.00649 AC: 277 AN: 42706

Ashkenazi Jewish (ASJ) AF: 0.00728 AC: 187 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39008

South Asian (SAS) AF: 0.00233 AC: 194 AN: 83238

European-Finnish (FIN) AF: 0.000507 AC: 26 AN: 51292

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5746

European-Non Finnish (NFE) AF: 0.00139 AC: 1540 AN: 1104992

Other (OTH) AF: 0.00384 AC: 230 AN: 59818

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74430

African (AFR) AF: 0.000457 AC: 19 AN: 41554

American (AMR) AF: 0.00908 AC: 139 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68012

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00230 Hom.: 5

Bravo AF: 0.00277

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFAP298: BP4, BS2; CFAP298-TCP10L: BP4, BS2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.95	T
PhyloP100		2.4
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.074
Sift	Benign	0.25	T
Sift4G	Benign	0.39	T
Polyphen		0.0040	B
Vest4		0.20
MVP		0.14
MPC		0.15
ClinPred		0.030	T
GERP RS		3.7
PromoterAI		-0.087	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.35
gMVP		0.38
Mutation Taster		=49/51	disease causing

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: rs138178722; hg19: chr21-33984477; COSMIC: COSV106090410; COSMIC: COSV106090410;