rs2985696

Variant names:

• chr14-49628195-C-A
• rs2985696
• NM_018139.3:c.1864-40G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018139.3(DNAAF2):​c.1864-40G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,510,446 control chromosomes in the GnomAD database, including 407,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38278 hom., cov: 32)
  • Exomes 𝑓: 0.73 (368878 hom.)
• Consequence: DNAAF2 NM_018139.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.228
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-49628195-C-A is Benign according to our data. Variant chr14-49628195-C-A is described in ClinVar as Benign. ClinVar VariationId is 261017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.1864-40G>T		intron_variant	Intron 1 of 2	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.1864-2147G>T		intron_variant	Intron 1 of 1		NP_001077377.1
DNAAF2	NM_001378453.1	c.-204-2147G>T		intron_variant	Intron 1 of 1		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1864-40G>T		intron_variant	Intron 1 of 2	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.1864-2147G>T		intron_variant	Intron 1 of 1	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106053 AN: 151982 Hom.: 38249 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.653 AC: 106925 AN: 163780 AF XY: 0.649

Gnomad AFR exome AF: 0.631

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.778

Gnomad NFE exome AF: 0.754

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.727 AC: 986851 AN: 1358348 Hom.: 368878 Cov.: 22 AF XY: 0.722 AC XY: 485326 AN XY: 672304

African (AFR) AF: 0.641 AC: 19510 AN: 30454

American (AMR) AF: 0.631 AC: 21076 AN: 33390

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 18046 AN: 24520

East Asian (EAS) AF: 0.118 AC: 4421 AN: 37530

South Asian (SAS) AF: 0.546 AC: 41627 AN: 76194

European-Finnish (FIN) AF: 0.775 AC: 38592 AN: 49826

Middle Eastern (MID) AF: 0.677 AC: 3041 AN: 4494

European-Non Finnish (NFE) AF: 0.767 AC: 801439 AN: 1045378

Other (OTH) AF: 0.691 AC: 39099 AN: 56562

GnomAD4 genome AF: 0.698 AC: 106132 AN: 152098 Hom.: 38278 Cov.: 32 AF XY: 0.694 AC XY: 51585 AN XY: 74350

African (AFR) AF: 0.651 AC: 26998 AN: 41476

American (AMR) AF: 0.687 AC: 10496 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2525 AN: 3466

East Asian (EAS) AF: 0.148 AC: 764 AN: 5160

South Asian (SAS) AF: 0.533 AC: 2564 AN: 4814

European-Finnish (FIN) AF: 0.795 AC: 8424 AN: 10590

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51910 AN: 67994

Other (OTH) AF: 0.701 AC: 1479 AN: 2110

Alfa AF: 0.727 Hom.: 14160

Bravo AF: 0.686

Asia WGS AF: 0.401 AC: 1393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.33
PhyloP100		0.23
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: rs2985696; hg19: chr14-50094913; COSMIC: COSV53568238; COSMIC: COSV53568238;