rs576683556

Variant names:

• chr17-74291094-T-G
• rs576683556
• NM_023036.6:c.685T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_023036.6(DNAI2):​c.685T>G​(p.Ser229Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.10
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017565459).
• BP6: Variant 17-74291094-T-G is Benign according to our data. Variant chr17-74291094-T-G is described in ClinVar as Benign. ClinVar VariationId is 454940.Status of the report is criteria_provided_single_submitter, 1 stars.

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.685T>G	p.Ser229Ala	missense	Exon 6 of 14	NP_075462.3	Q9GZS0-1
	DNAI2	NM_001353167.2		c.685T>G	p.Ser229Ala	missense	Exon 6 of 15	NP_001340096.1
	DNAI2	NM_001172810.3		c.685T>G	p.Ser229Ala	missense	Exon 6 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.685T>G	p.Ser229Ala	missense	Exon 6 of 14	ENSP00000308312.6	Q9GZS0-1
	DNAI2	ENST00000579490.5	TSL:1	c.856T>G	p.Ser286Ala	missense	Exon 5 of 13	ENSP00000464197.1	J3QRG2
	DNAI2	ENST00000446837.2	TSL:1	c.685T>G	p.Ser229Ala	missense	Exon 5 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 32

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: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000258 AC: 65 AN: 251490 AF XY: 0.000375

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461874 Hom.: 1 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 727242

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00226 AC: 195 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000681 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000338 AC: 41

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.038
Sift	Benign	0.20	T
Sift4G	Benign	0.38	T
Polyphen		0.0020	B
Vest4		0.33
MutPred		0.51		Loss of disorder (P = 0.0915)
MVP		0.14
MPC		0.20
ClinPred		0.021	T
GERP RS		-0.93
Varity_R		0.084
gMVP		0.058
Mutation Taster		=94/6	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: rs576683556; hg19: chr17-72287233;