chr14-49634785-G-C

Variant names:

• chr14-49634785-G-C
• rs958625302
• NM_018139.3:c.365C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018139.3(DNAAF2):​c.365C>G​(p.Pro122Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P122L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• Publications: 0 publications found

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

DNAAF2 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 10

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.365C>G	p.Pro122Arg	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.365C>G	p.Pro122Arg	missense_variant	Exon 1 of 2		NP_001077377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.365C>G	p.Pro122Arg	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.365C>G	p.Pro122Arg	missense_variant	Exon 1 of 2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 98

GnomAD4 genome Cov.: 35

Alfa AF: 0.0000306 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.67		Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.044	Neutral
Varity_R		0.84
gMVP		0.96
Mutation Taster		=24/76	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: rs958625302; hg19: chr14-50101503;