chr17-74312223-C-T

Position:

• chr17-74312223-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_023036.6(DNAI2):​c.1715C>T​(p.Pro572Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,578,290 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P572P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0013 (9 hom.)
• Consequence: DNAI2 NM_023036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.535

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]

LOC105371891 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007289797).
• BP6: Variant 17-74312223-C-T is Benign according to our data. Variant chr17-74312223-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261644.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00105 (150/143340) while in subpopulation SAS AF= 0.00832 (36/4326). AF 95% confidence interval is 0.00618. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI2	NM_023036.6	c.1715C>T	p.Pro572Leu	missense_variant	12/14	ENST00000311014.11
LOC105371891	XR_934971.3	n.277-38G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI2	ENST00000311014.11	c.1715C>T	p.Pro572Leu	missense_variant	12/14	1	NM_023036.6	P2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 151 AN: 143212 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000665

Gnomad SAS AF: 0.00856

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00150

GnomAD3 exomes AF: 0.00154 AC: 325 AN: 210886 Hom.: 1 AF XY: 0.00191 AC XY: 218 AN XY: 114200

Gnomad AFR exome AF: 0.000157

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000636

Gnomad SAS exome AF: 0.00680

Gnomad FIN exome AF: 0.00230

Gnomad NFE exome AF: 0.000911

Gnomad OTH exome AF: 0.000746

GnomAD4 exome AF: 0.00134 AC: 1917 AN: 1434950 Hom.: 9 Cov.: 36 AF XY: 0.00153 AC XY: 1090 AN XY: 712290

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00673

Gnomad4 FIN exome AF: 0.00265

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00105 AC: 150 AN: 143340 Hom.: 0 Cov.: 29 AF XY: 0.00123 AC XY: 85 AN XY: 69346

Gnomad4 AFR AF: 0.000307

Gnomad4 AMR AF: 0.000142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000665

Gnomad4 SAS AF: 0.00832

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00149

Alfa AF: 0.000854 Hom.: 0

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Aug 22, 2017	BP4, BP6; This alteration is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -

Primary ciliary dyskinesia 9 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.012	.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.60	T;.;T;T
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.70	.;N;N;.
REVEL	Benign	0.064
Sift	Benign	0.076	.;T;T;.
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0050	.;B;B;.
Vest4		0.22
MVP		0.47
MPC		0.26
ClinPred		0.0033	T
GERP RS		-1.6
Varity_R		0.032
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs151241589; hg19: chr17-72308362;