17-74309395-C-T

Variant names:

• chr17-74309395-C-T
• rs2290955
• NM_023036.6:c.1347+7C>T

Variant summary

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

The NM_023036.6(DNAI2):​c.1347+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,613,576 control chromosomes in the GnomAD database, including 300,890 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19944 hom., cov: 31)
  • Exomes 𝑓: 0.61 (280946 hom.)
• Consequence: DNAI2 NM_023036.6 splice_region, intron
• Scores: Splicing: ADA: 0.0008948
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.52
• Publications: 10 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

ENSG00000266106 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-74309395-C-T is Benign according to our data. Variant chr17-74309395-C-T is described in ClinVar as Benign. ClinVar VariationId is 163169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.1347+7C>T		splice_region_variant, intron_variant	Intron 10 of 13	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.1347+7C>T		splice_region_variant, intron_variant	Intron 10 of 13	1	NM_023036.6	ENSP00000308312.6

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71690 AN: 151900 Hom.: 19945 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.523 AC: 131183 AN: 250868 AF XY: 0.542

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.252

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.609 AC: 890505 AN: 1461558 Hom.: 280946 Cov.: 62 AF XY: 0.611 AC XY: 444175 AN XY: 727074

African (AFR) AF: 0.169 AC: 5645 AN: 33478

American (AMR) AF: 0.339 AC: 15165 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 14496 AN: 26132

East Asian (EAS) AF: 0.264 AC: 10462 AN: 39694

South Asian (SAS) AF: 0.566 AC: 48797 AN: 86230

European-Finnish (FIN) AF: 0.612 AC: 32649 AN: 53390

Middle Eastern (MID) AF: 0.504 AC: 2905 AN: 5766

European-Non Finnish (NFE) AF: 0.654 AC: 726856 AN: 1111786

Other (OTH) AF: 0.555 AC: 33530 AN: 60392

GnomAD4 genome AF: 0.472 AC: 71680 AN: 152018 Hom.: 19944 Cov.: 31 AF XY: 0.468 AC XY: 34731 AN XY: 74286

African (AFR) AF: 0.184 AC: 7610 AN: 41462

American (AMR) AF: 0.399 AC: 6105 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3470

East Asian (EAS) AF: 0.258 AC: 1325 AN: 5142

South Asian (SAS) AF: 0.554 AC: 2672 AN: 4826

European-Finnish (FIN) AF: 0.592 AC: 6247 AN: 10544

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44130 AN: 67978

Other (OTH) AF: 0.463 AC: 976 AN: 2108

Alfa AF: 0.596 Hom.: 25419

Bravo AF: 0.441

Asia WGS AF: 0.376 AC: 1310 AN: 3478

EpiCase AF: 0.632

EpiControl AF: 0.635

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1347+7C>T in intron 10 of DNAI2: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 35.6% (3065/8600) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs2290955). -

Primary ciliary dyskinesia 9 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.75
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00089
dbscSNV1_RF	Benign	0.022
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: rs2290955; hg19: chr17-72305534; COSMIC: COSV56758796; COSMIC: COSV56758796;