rs1060502201

Positions:

• chr17-74291047-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_023036.6(DNAI2):​c.638T>G​(p.Leu213Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI2	NM_023036.6	c.638T>G	p.Leu213Arg	missense_variant	6/14	ENST00000311014.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11	c.638T>G	p.Leu213Arg	missense_variant	6/14	1	NM_023036.6	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DNAI2-related disease. This sequence change replaces leucine with arginine at codon 213 of the DNAI2 protein (p.Leu213Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.1	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.4	.;D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.80
MutPred		0.63		Loss of stability (P = 0.0248);Loss of stability (P = 0.0248);Loss of stability (P = 0.0248);.;
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502201; hg19: chr17-72287186;