14-49633668-T-C

Variant names:

• chr14-49633668-T-C
• rs2985687
• NM_018139.3:c.1482A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000298292.13(DNAAF2):​c.1482A>G​(p.Thr494Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,610,450 control chromosomes in the GnomAD database, including 423,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33831 hom., cov: 32)
  • Exomes 𝑓: 0.72 (389892 hom.)
• Consequence: DNAAF2 ENST00000298292.13 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.79
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-49633668-T-C is Benign according to our data. Variant chr14-49633668-T-C is described in ClinVar as Benign. ClinVar VariationId is 95892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000298292.13. 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.1482A>G	p.Thr494Thr	synonymous	Exon 1 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.1482A>G	p.Thr494Thr	synonymous	Exon 1 of 2	NP_001077377.1
	DNAAF2	NM_001378453.1		c.-390A>G		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.1482A>G	p.Thr494Thr	synonymous	Exon 1 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.1482A>G	p.Thr494Thr	synonymous	Exon 1 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98327 AN: 151856 Hom.: 33816 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.670

GnomAD2 exomes AF: 0.648 AC: 161163 AN: 248550 AF XY: 0.652

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.601

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.780

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.720 AC: 1050070 AN: 1458478 Hom.: 389892 Cov.: 91 AF XY: 0.716 AC XY: 519182 AN XY: 725110

African (AFR) AF: 0.472 AC: 15767 AN: 33374

American (AMR) AF: 0.611 AC: 27222 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 18771 AN: 26072

East Asian (EAS) AF: 0.122 AC: 4825 AN: 39644

South Asian (SAS) AF: 0.547 AC: 47148 AN: 86174

European-Finnish (FIN) AF: 0.775 AC: 40846 AN: 52700

Middle Eastern (MID) AF: 0.653 AC: 3756 AN: 5756

European-Non Finnish (NFE) AF: 0.767 AC: 850804 AN: 1109966

Other (OTH) AF: 0.679 AC: 40931 AN: 60264

GnomAD4 genome AF: 0.647 AC: 98395 AN: 151972 Hom.: 33831 Cov.: 32 AF XY: 0.645 AC XY: 47934 AN XY: 74294

African (AFR) AF: 0.483 AC: 19996 AN: 41434

American (AMR) AF: 0.661 AC: 10107 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2472 AN: 3472

East Asian (EAS) AF: 0.149 AC: 762 AN: 5126

South Asian (SAS) AF: 0.533 AC: 2567 AN: 4816

European-Finnish (FIN) AF: 0.795 AC: 8423 AN: 10592

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51691 AN: 67926

Other (OTH) AF: 0.670 AC: 1414 AN: 2110

Alfa AF: 0.720 Hom.: 28275

Bravo AF: 0.629

Asia WGS AF: 0.392 AC: 1362 AN: 3478

EpiCase AF: 0.755

EpiControl AF: 0.765

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.63
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2985687; hg19: chr14-50100386; COSMIC: COSV53568251; COSMIC: COSV53568251;