17-74299691-C-T

Variant names:

• chr17-74299691-C-T
• rs72848284
• NM_023036.6:c.725-27C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_023036.6(DNAI2):​c.725-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 1,612,962 control chromosomes in the GnomAD database, including 1,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1296 hom.)
• Consequence: DNAI2 NM_023036.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.688
• Publications: 0 publications found

Genes affected

DNAI2 (HGNC:18744): (dynein axonemal intermediate chain 2) The protein encoded by this gene belongs to the dynein intermediate chain family, and is part of the dynein complex of respiratory cilia and sperm flagella. Mutations in this gene are associated with primary ciliary dyskinesia type 9. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

DNAI2 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), 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=-0.82).
• BP6: Variant 17-74299691-C-T is Benign according to our data. Variant chr17-74299691-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0269 (4104/152284) while in subpopulation NFE AF = 0.0408 (2773/68020). AF 95% confidence interval is 0.0395. There are 85 homozygotes in GnomAd4. There are 1976 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.725-27C>T		intron_variant	Intron 6 of 13	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.725-27C>T		intron_variant	Intron 6 of 13	1	NM_023036.6	ENSP00000308312.6

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4103 AN: 152166 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0588

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0265 AC: 6609 AN: 249632 AF XY: 0.0270

Gnomad AFR exome AF: 0.00643

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0607

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0265

GnomAD4 exome AF: 0.0380 AC: 55506 AN: 1460678 Hom.: 1296 Cov.: 32 AF XY: 0.0370 AC XY: 26855 AN XY: 726602

African (AFR) AF: 0.00556 AC: 186 AN: 33476

American (AMR) AF: 0.00962 AC: 430 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00598 AC: 516 AN: 86252

European-Finnish (FIN) AF: 0.0603 AC: 3156 AN: 52356

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.0442 AC: 49125 AN: 1111898

Other (OTH) AF: 0.0322 AC: 1946 AN: 60378

GnomAD4 genome AF: 0.0269 AC: 4104 AN: 152284 Hom.: 85 Cov.: 32 AF XY: 0.0265 AC XY: 1976 AN XY: 74458

African (AFR) AF: 0.00686 AC: 285 AN: 41558

American (AMR) AF: 0.0167 AC: 256 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.0588 AC: 624 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2773 AN: 68020

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0294 Hom.: 15

Bravo AF: 0.0235

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.82
CADD	Benign	2.5
DANN	Benign	0.58
PhyloP100		0.69
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: rs72848284; hg19: chr17-72295830;