rs117932646

Variant names:

• chr17-74312168-G-A
• rs117932646
• NM_023036.6:c.1660G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-74312168-G-A
• chr17-74312168-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D554H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (19 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.391
• Publications: 4 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

ENSG00000309634 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.1660G>A	p.Asp554Asn	missense	Exon 12 of 14	NP_075462.3	Q9GZS0-1
	DNAI2	NM_001353167.2		c.1660G>A	p.Asp554Asn	missense	Exon 12 of 15	NP_001340096.1
	DNAI2	NM_001172810.3		c.1624G>A	p.Asp542Asn	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.1660G>A	p.Asp554Asn	missense	Exon 12 of 14	ENSP00000308312.6	Q9GZS0-1
	DNAI2	ENST00000579490.5	TSL:1	c.1831G>A	p.Asp611Asn	missense	Exon 11 of 13	ENSP00000464197.1	J3QRG2
	DNAI2	ENST00000446837.2	TSL:1	c.1660G>A	p.Asp554Asn	missense	Exon 11 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 265 AN: 148876 Hom.: 4 Cov.: 33

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

GnomAD2 exomes AF: 0.00353 AC: 877 AN: 248576 AF XY: 0.00325

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 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

African (AFR) AF: 0.0000644 AC: 2 AN: 31060

American (AMR) AF: 0.000118 AC: 5 AN: 42286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23300

East Asian (EAS) AF: 0.0280 AC: 920 AN: 32902

South Asian (SAS) AF: 0.000246 AC: 21 AN: 85486

European-Finnish (FIN) AF: 0.0140 AC: 652 AN: 46448

Middle Eastern (MID) AF: 0.000379 AC: 2 AN: 5274

European-Non Finnish (NFE) AF: 0.000366 AC: 389 AN: 1062298

Other (OTH) AF: 0.00221 AC: 122 AN: 55296

GnomAD4 genome AF: 0.00178 AC: 265 AN: 149002 Hom.: 4 Cov.: 33 AF XY: 0.00220 AC XY: 160 AN XY: 72620

African (AFR) AF: 0.00 AC: 0 AN: 40876

American (AMR) AF: 0.000268 AC: 4 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.0229 AC: 111 AN: 4850

South Asian (SAS) AF: 0.000654 AC: 3 AN: 4586

European-Finnish (FIN) AF: 0.0116 AC: 115 AN: 9932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000417 AC: 28 AN: 67134

Other (OTH) AF: 0.00192 AC: 4 AN: 2080

Alfa AF: 0.00110 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	Primary ciliary dyskinesia 9 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.39
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.47	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	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
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: rs117932646; hg19: chr17-72308307;