chr17-74312180-G-A

Variant names:

• chr17-74312180-G-A
• rs1979370
• NM_023036.6:c.1672G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023036.6(DNAI2):​c.1672G>A​(p.Ala558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,610,478 control chromosomes in the GnomAD database, including 631,593 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A558A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (48710 hom., cov: 27)
  • Exomes 𝑓: 0.89 (582883 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.17
• Publications: 31 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=6.3897465E-7).
• BP6: Variant 17-74312180-G-A is Benign according to our data. Variant chr17-74312180-G-A is described in ClinVar as Benign. ClinVar VariationId is 163171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

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.1672G>A	p.Ala558Thr	missense	Exon 12 of 14	NP_075462.3	Q9GZS0-1
	DNAI2	NM_001353167.2		c.1672G>A	p.Ala558Thr	missense	Exon 12 of 15	NP_001340096.1
	DNAI2	NM_001172810.3		c.1636G>A	p.Ala546Thr	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.1672G>A	p.Ala558Thr	missense	Exon 12 of 14	ENSP00000308312.6	Q9GZS0-1
	DNAI2	ENST00000579490.5	TSL:1	c.1843G>A	p.Ala615Thr	missense	Exon 11 of 13	ENSP00000464197.1	J3QRG2
	DNAI2	ENST00000446837.2	TSL:1	c.1672G>A	p.Ala558Thr	missense	Exon 11 of 13	ENSP00000400252.2	Q9GZS0-1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118272 AN: 151280 Hom.: 48707 Cov.: 27

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.799

GnomAD2 exomes AF: 0.864 AC: 213610 AN: 247294 AF XY: 0.868

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.933

Gnomad ASJ exome AF: 0.881

Gnomad EAS exome AF: 0.848

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.903

Gnomad OTH exome AF: 0.878

GnomAD4 exome AF: 0.892 AC: 1300812 AN: 1459080 Hom.: 582883 Cov.: 70 AF XY: 0.891 AC XY: 646683 AN XY: 725786

African (AFR) AF: 0.481 AC: 15780 AN: 32812

American (AMR) AF: 0.927 AC: 41353 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 23070 AN: 26098

East Asian (EAS) AF: 0.850 AC: 33532 AN: 39456

South Asian (SAS) AF: 0.832 AC: 71679 AN: 86102

European-Finnish (FIN) AF: 0.891 AC: 47248 AN: 53006

Middle Eastern (MID) AF: 0.853 AC: 4839 AN: 5672

European-Non Finnish (NFE) AF: 0.910 AC: 1011379 AN: 1111156

Other (OTH) AF: 0.863 AC: 51932 AN: 60190

GnomAD4 genome AF: 0.781 AC: 118299 AN: 151398 Hom.: 48710 Cov.: 27 AF XY: 0.784 AC XY: 57965 AN XY: 73930

African (AFR) AF: 0.490 AC: 20165 AN: 41148

American (AMR) AF: 0.883 AC: 13432 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3083 AN: 3466

East Asian (EAS) AF: 0.842 AC: 4260 AN: 5062

South Asian (SAS) AF: 0.826 AC: 3951 AN: 4782

European-Finnish (FIN) AF: 0.879 AC: 9236 AN: 10504

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61460 AN: 67934

Other (OTH) AF: 0.798 AC: 1670 AN: 2094

Alfa AF: 0.866 Hom.: 234996

Bravo AF: 0.769

TwinsUK AF: 0.912 AC: 3381

ALSPAC AF: 0.919 AC: 3543

ESP6500AA AF: 0.497 AC: 2189

ESP6500EA AF: 0.910 AC: 7829

ExAC AF: 0.852 AC: 103350

Asia WGS AF: 0.808 AC: 2808 AN: 3478

EpiCase AF: 0.902

EpiControl AF: 0.904

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Primary ciliary dyskinesia (3)
-	-	3	Primary ciliary dyskinesia 9 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0040
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		-2.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.076
Sift	Benign	0.45	T
Sift4G	Benign	0.60	T
Polyphen		0.0020	B
Vest4		0.050
MPC		0.23
ClinPred		0.027	T
GERP RS		-9.4
Varity_R		0.027
gMVP		0.36
Mutation Taster		=19/81	disease causing

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: rs1979370; hg19: chr17-72308319; COSMIC: COSV56758937; COSMIC: COSV56758937;