NM_023036.6:c.787C>G

Variant names:

• chr17-74299780-C-G
• rs137852998
• NM_023036.6:c.787C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_023036.6(DNAI2):​c.787C>G​(p.Arg263Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.63
• Publications: 12 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

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.787C>G	p.Arg263Gly	missense	Exon 7 of 14	NP_075462.3	Q9GZS0-1
	DNAI2	NM_001353167.2		c.787C>G	p.Arg263Gly	missense	Exon 7 of 15	NP_001340096.1
	DNAI2	NM_001172810.3		c.787C>G	p.Arg263Gly	missense	Exon 7 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.787C>G	p.Arg263Gly	missense	Exon 7 of 14	ENSP00000308312.6	Q9GZS0-1
	DNAI2	ENST00000579490.5	TSL:1	c.958C>G	p.Arg320Gly	missense	Exon 6 of 13	ENSP00000464197.1	J3QRG2
	DNAI2	ENST00000446837.2	TSL:1	c.787C>G	p.Arg263Gly	missense	Exon 6 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250516 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461232 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726886

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	Primary ciliary dyskinesia 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.52		Loss of stability (P = 0.0346)
MVP		0.95
MPC		0.90
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.78
gMVP		0.27
Mutation Taster		=63/37	polymorphism

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: rs137852998; hg19: chr17-72295919;