17-74274303-A-G

Variant names:

• chr17-74274303-A-G
• rs1877687
• NM_023036.6:c.-54A>G

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.-54A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,812 control chromosomes in the GnomAD database, including 22,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22853 hom., cov: 31)
  • Exomes 𝑓: 0.63 (8 hom.)
• Consequence: DNAI2 NM_023036.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.367
• Publications: 6 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=-0.87).
• BP6: Variant 17-74274303-A-G is Benign according to our data. Variant chr17-74274303-A-G is described in ClinVar as [Benign]. Clinvar id is 325001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.-54A>G		5_prime_UTR_variant	Exon 1 of 14	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.-54A>G		5_prime_UTR_variant	Exon 1 of 14	1	NM_023036.6	ENSP00000308312.6
DNAI2	ENST00000582036.5	c.-51A>G		5_prime_UTR_variant	Exon 1 of 14	1		ENSP00000461950.1
DNAI2	ENST00000579055.5	n.-54A>G		non_coding_transcript_exon_variant	Exon 1 of 13	2		ENSP00000462767.1
DNAI2	ENST00000579055.5	n.-54A>G		5_prime_UTR_variant	Exon 1 of 13	2		ENSP00000462767.1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82407 AN: 151652 Hom.: 22816 Cov.: 31

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.616

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.625 AC: 25 AN: 40 Hom.: 8 Cov.: 0 AF XY: 0.676 AC XY: 23 AN XY: 34

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 8 AN: 12

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.563 AC: 9 AN: 16

Other (OTH) AF: 0.500 AC: 4 AN: 8

GnomAD4 genome AF: 0.544 AC: 82492 AN: 151772 Hom.: 22853 Cov.: 31 AF XY: 0.549 AC XY: 40738 AN XY: 74160

African (AFR) AF: 0.596 AC: 24655 AN: 41384

American (AMR) AF: 0.565 AC: 8604 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1794 AN: 3468

East Asian (EAS) AF: 0.801 AC: 4118 AN: 5144

South Asian (SAS) AF: 0.607 AC: 2912 AN: 4794

European-Finnish (FIN) AF: 0.549 AC: 5798 AN: 10558

Middle Eastern (MID) AF: 0.628 AC: 182 AN: 290

European-Non Finnish (NFE) AF: 0.485 AC: 32892 AN: 67888

Other (OTH) AF: 0.549 AC: 1157 AN: 2106

Alfa AF: 0.513 Hom.: 39036

Bravo AF: 0.546

Asia WGS AF: 0.719 AC: 2497 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 9 Benign:1

Jan 12, 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. -

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	-0.87
CADD	Benign	8.0
DANN	Benign	0.43
PhyloP100		0.37
PromoterAI		0.021	Neutral
Mutation Taster		=300/0	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: rs1877687; hg19: chr17-72270442;