17-74309395-C-T

Variant summary

Our verdict is Benign. Variant got -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:8
• Conservation: PhyloP100: -1.52

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 163169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74309395-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DNAI2	NM_023036.6	c.1347+7C>T		splice_region_variant, intron_variant		ENST00000311014.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11	c.1347+7C>T		splice_region_variant, intron_variant		1	NM_023036.6	P2
	ENST00000585167.1	n.396G>A		non_coding_transcript_exon_variant	1/2	3

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

GnomAD3 exomes AF: 0.523 AC: 131183 AN: 250868 Hom.: 37762 AF XY: 0.542 AC XY: 73557 AN XY: 135612

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 SAS exome AF: 0.566

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

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.566

Gnomad4 FIN exome AF: 0.612

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.555

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

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.554

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.649

Gnomad4 OTH AF: 0.463

Alfa AF: 0.597 Hom.: 23893

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 9 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Primary ciliary dyskinesia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.3
Dann	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs2290955; hg19: chr17-72305534; COSMIC: COSV56758796; COSMIC: COSV56758796;