14-49633656-C-T

Variant names:

• chr14-49633656-C-T
• rs2985688
• NM_018139.3:c.1494G>A

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.1494G>A​(p.Ser498Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,612,306 control chromosomes in the GnomAD database, including 40 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 0.0048 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (33 hom.)
• Consequence: DNAAF2 NM_018139.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.970
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-49633656-C-T is Benign according to our data. Variant chr14-49633656-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261013.
• BP7: Synonymous conserved (PhyloP=-0.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00477 (726/152320) while in subpopulation SAS AF = 0.00621 (30/4830). AF 95% confidence interval is 0.00461. There are 7 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.1494G>A	p.Ser498Ser	synonymous	Exon 1 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.1494G>A	p.Ser498Ser	synonymous	Exon 1 of 2	NP_001077377.1
	DNAAF2	NM_001378453.1		c.-378G>A		5_prime_UTR	Exon 1 of 2	NP_001365382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.1494G>A	p.Ser498Ser	synonymous	Exon 1 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.1494G>A	p.Ser498Ser	synonymous	Exon 1 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152202 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00510 AC: 1270 AN: 249192 AF XY: 0.00505

Gnomad AFR exome AF: 0.00598

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00304 AC: 4433 AN: 1459986 Hom.: 33 Cov.: 31 AF XY: 0.00315 AC XY: 2288 AN XY: 726106

African (AFR) AF: 0.00566 AC: 189 AN: 33420

American (AMR) AF: 0.00244 AC: 109 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26094

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39678

South Asian (SAS) AF: 0.00722 AC: 623 AN: 86230

European-Finnish (FIN) AF: 0.0267 AC: 1415 AN: 52918

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5764

European-Non Finnish (NFE) AF: 0.00160 AC: 1776 AN: 1110926

Other (OTH) AF: 0.00406 AC: 245 AN: 60312

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152320 Hom.: 7 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74496

African (AFR) AF: 0.00517 AC: 215 AN: 41558

American (AMR) AF: 0.00281 AC: 43 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.0276 AC: 293 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 68024

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00278

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00243

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.8
DANN	Benign	0.82
PhyloP100		-0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2985688; hg19: chr14-50100374; COSMIC: COSV53569503; COSMIC: COSV53569503;