17-74312168-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_023036.6(DNAI2):​c.1660G>A​(p.Asp554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,533,352 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 4 hom., cov: 33)
Exomes 𝑓: 0.0015 ( 19 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.391
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0027095377).
BP6
Variant 17-74312168-G-A is Benign according to our data. Variant chr17-74312168-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 325023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00178 (265/149002) while in subpopulation EAS AF= 0.0229 (111/4850). AF 95% confidence interval is 0.0194. There are 4 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAI2NM_023036.6 linkuse as main transcriptc.1660G>A p.Asp554Asn missense_variant 12/14 ENST00000311014.11 NP_075462.3
LOC105371891XR_934971.3 linkuse as main transcriptn.294C>T non_coding_transcript_exon_variant 3/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAI2ENST00000311014.11 linkuse as main transcriptc.1660G>A p.Asp554Asn missense_variant 12/141 NM_023036.6 ENSP00000308312 P2Q9GZS0-1

Frequencies

GnomAD3 genomes
AF:
0.00178
AC:
265
AN:
148876
Hom.:
4
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000268
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0228
Gnomad SAS
AF:
0.000654
Gnomad FIN
AF:
0.0116
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000417
Gnomad OTH
AF:
0.00194
GnomAD3 exomes
AF:
0.00353
AC:
877
AN:
248576
Hom.:
13
AF XY:
0.00325
AC XY:
438
AN XY:
134730
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0253
Gnomad SAS exome
AF:
0.000295
Gnomad FIN exome
AF:
0.0132
Gnomad NFE exome
AF:
0.000958
Gnomad OTH exome
AF:
0.00165
GnomAD4 exome
AF:
0.00153
AC:
2113
AN:
1384350
Hom.:
19
Cov.:
33
AF XY:
0.00146
AC XY:
1007
AN XY:
687742
show subpopulations
Gnomad4 AFR exome
AF:
0.0000644
Gnomad4 AMR exome
AF:
0.000118
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0280
Gnomad4 SAS exome
AF:
0.000246
Gnomad4 FIN exome
AF:
0.0140
Gnomad4 NFE exome
AF:
0.000366
Gnomad4 OTH exome
AF:
0.00221
GnomAD4 genome
AF:
0.00178
AC:
265
AN:
149002
Hom.:
4
Cov.:
33
AF XY:
0.00220
AC XY:
160
AN XY:
72620
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000268
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0229
Gnomad4 SAS
AF:
0.000654
Gnomad4 FIN
AF:
0.0116
Gnomad4 NFE
AF:
0.000417
Gnomad4 OTH
AF:
0.00192
Alfa
AF:
0.00126
Hom.:
1
Bravo
AF:
0.00102
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.00348
AC:
422
Asia WGS
AF:
0.00549
AC:
19
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000297

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Benign:3
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 30, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Primary ciliary dyskinesia 9 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.63
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
2.3
DANN
Benign
0.83
DEOGEN2
Benign
0.0041
.;T;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.098
N
LIST_S2
Benign
0.75
T;.;T;T
MetaRNN
Benign
0.0027
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
.;L;L;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.1
.;N;N;.
REVEL
Benign
0.038
Sift
Benign
0.47
.;T;T;.
Sift4G
Benign
0.60
T;T;T;T
Polyphen
0.0040
.;B;B;.
Vest4
0.10
MVP
0.59
MPC
0.23
ClinPred
0.024
T
GERP RS
-1.1
Varity_R
0.032
gMVP
0.44

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs117932646; hg19: chr17-72308307; API