chr2-119601378-G-A

Variant names:

• chr2-119601378-G-A
• rs770962526
• NM_001271049.2:c.791+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001271049.2(CFAP221):​c.791+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000111 in 1,354,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CFAP221 NM_001271049.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54

Genes affected

CFAP221 (HGNC:33720): (cilia and flagella associated protein 221) Predicted to enable calmodulin binding activity. Predicted to be involved in cilium assembly. Predicted to act upstream of or within cerebrospinal fluid circulation; motile cilium assembly; and mucociliary clearance. Predicted to be located in axoneme; extracellular region; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP221	NM_001271049.2	c.791+1G>A		splice_donor_variant, intron_variant	Intron 8 of 23	ENST00000413369.8	NP_001257978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP221	ENST00000413369.8	c.791+1G>A		splice_donor_variant, intron_variant	Intron 8 of 23	5	NM_001271049.2	ENSP00000393222.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000232 AC: 3 AN: 129394 AF XY: 0.0000285

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 15 AN: 1354336 Hom.: 0 Cov.: 31 AF XY: 0.00000905 AC XY: 6 AN XY: 662742

African (AFR) AF: 0.00 AC: 0 AN: 31106

American (AMR) AF: 0.0000294 AC: 1 AN: 33992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24708

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34972

South Asian (SAS) AF: 0.0000264 AC: 2 AN: 75880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.0000104 AC: 11 AN: 1057958

Other (OTH) AF: 0.00 AC: 0 AN: 56602

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000633 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		4.9
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs770962526; hg19: chr2-120358954;