rs34352773

Variant names:

• chr14-49628066-T-C
• rs34352773
• NM_018139.3:c.1953A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-49628066-T-C
• chr14-49628066-T-A
• chr14-49628066-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_018139.3(DNAAF2):​c.1953A>G​(p.Pro651Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,579,680 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (13 hom.)
• Consequence: DNAAF2 NM_018139.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.713
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 14-49628066-T-C is Benign according to our data. Variant chr14-49628066-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195338.
• BP7: Synonymous conserved (PhyloP=0.713 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00298 (454/152284) while in subpopulation AMR AF = 0.00569 (87/15292). AF 95% confidence interval is 0.00472. There are 6 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018139.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.1953A>G	p.Pro651Pro	synonymous	Exon 2 of 3	NP_060609.2	Q9NVR5-1
	DNAAF2	NM_001083908.2		c.1864-2018A>G		intron	N/A	NP_001077377.1	Q9NVR5-2
	DNAAF2	NM_001378453.1		c.-204-2018A>G		intron	N/A	NP_001365382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.1953A>G	p.Pro651Pro	synonymous	Exon 2 of 3	ENSP00000298292.8	Q9NVR5-1
	DNAAF2	ENST00000406043.3	TSL:1	c.1864-2018A>G		intron	N/A	ENSP00000384862.3	Q9NVR5-2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152166 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00247 AC: 496 AN: 200802 AF XY: 0.00236

Gnomad AFR exome AF: 0.000540

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00877

Gnomad EAS exome AF: 0.0000638

Gnomad FIN exome AF: 0.000259

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00413

GnomAD4 exome AF: 0.00221 AC: 3153 AN: 1427396 Hom.: 13 Cov.: 30 AF XY: 0.00226 AC XY: 1596 AN XY: 706436

African (AFR) AF: 0.00113 AC: 37 AN: 32840

American (AMR) AF: 0.00466 AC: 183 AN: 39252

Ashkenazi Jewish (ASJ) AF: 0.00847 AC: 216 AN: 25510

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38948

South Asian (SAS) AF: 0.00132 AC: 107 AN: 81200

European-Finnish (FIN) AF: 0.000291 AC: 15 AN: 51594

Middle Eastern (MID) AF: 0.0175 AC: 100 AN: 5708

European-Non Finnish (NFE) AF: 0.00210 AC: 2294 AN: 1093142

Other (OTH) AF: 0.00338 AC: 200 AN: 59202

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152284 Hom.: 6 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74466

African (AFR) AF: 0.000505 AC: 21 AN: 41546

American (AMR) AF: 0.00569 AC: 87 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00287 AC: 195 AN: 68024

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00288 Hom.: 0

Bravo AF: 0.00376

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 10 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.2
DANN	Benign	0.73
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism

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: rs34352773; hg19: chr14-50094784; COSMIC: COSV53568786; COSMIC: COSV53568786;