17-74312108-G-T

Variant names:

• chr17-74312108-G-T
• rs538543314
• NM_023036.6:c.1600G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023036.6(DNAI2):​c.1600G>T​(p.Asp534Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D534N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371891 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18124041).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI2	NM_023036.6	MANE Select	c.1600G>T	p.Asp534Tyr	missense	Exon 12 of 14	NP_075462.3	Q9GZS0-1
	DNAI2	NM_001353167.2		c.1600G>T	p.Asp534Tyr	missense	Exon 12 of 15	NP_001340096.1
	DNAI2	NM_001172810.3		c.1564G>T	p.Asp522Tyr	missense	Exon 12 of 14	NP_001166281.1	Q9GZS0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI2	ENST00000311014.11	TSL:1 MANE Select	c.1600G>T	p.Asp534Tyr	missense	Exon 12 of 14	ENSP00000308312.6	Q9GZS0-1
	DNAI2	ENST00000579490.5	TSL:1	c.1771G>T	p.Asp591Tyr	missense	Exon 11 of 13	ENSP00000464197.1	J3QRG2
	DNAI2	ENST00000446837.2	TSL:1	c.1600G>T	p.Asp534Tyr	missense	Exon 11 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250366 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461370 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.040	D
Polyphen		0.013	B
Vest4		0.17
MutPred		0.35		Gain of phosphorylation at D534 (P = 0.0143)
MVP		0.72
MPC		0.30
ClinPred		0.12	T
GERP RS		-0.65
Varity_R		0.10
gMVP		0.63
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs538543314; hg19: chr17-72308247;