Variant chr17-74286974-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000311014.11(DNAI2):c.346-3T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNAI2
ENST00000311014.11 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9941

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.14

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-74286974-T-G is Pathogenic according to our data. Variant chr17-74286974-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI2	NM_023036.6 linkuse as main transcript	c.346-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11 linkuse as main transcript	c.346-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_023036.6	ENSP00000308312	P2	Q9GZS0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2008

- -

Primary ciliary dyskinesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 4 skipping and introduces a premature termination codon (PMID: 18950741). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 4954). This variant is also known as IVS3-3T>G. This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 18950741). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the DNAI2 gene. It does not directly change the encoded amino acid sequence of the DNAI2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2023

Non-canonical splice site variant demonstrated to result in loss of function (Loges et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32253119, 18950741) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.72

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.90

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over