rs200125805

Positions:

• chr17-74285152-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023036.6(DNAI2):​c.296A>C​(p.Lys99Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K99K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36578125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI2	NM_023036.6	c.296A>C	p.Lys99Thr	missense_variant	3/14	ENST00000311014.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11	c.296A>C	p.Lys99Thr	missense_variant	3/14	1	NM_023036.6	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2016	The p.K99T variant (also known as c.296A>C), located in coding exon 2 of the DNAI2 gene, results from an A to C substitution at nucleotide position 296. The lysine at codon 99 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs200125805. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.91% (1/110) Puerto Rican alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces lysine with threonine at codon 99 of the DNAI2 protein (p.Lys99Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs200125805, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with DNAI2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.6	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	.;D;D;.
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.57
MVP		0.50
MPC		0.94
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.37

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

Other links and lift over

dbSNP: rs200125805; hg19: chr17-72281291;