Variant chr2-171725629-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001378.3(DYNC1I2):c.523G>T(p.Asp175Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 142,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DYNC1I2
NM_001378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.08

Variant links:

Genes affected

DYNC1I2 (HGNC:2964): (dynein cytoplasmic 1 intermediate chain 2) This gene encodes a member of the dynein intermediate chain family. The encoded protein is a non-catalytic component of the cytoplasmic dynein 1 complex, which acts as a retrograde microtubule motor to transport organelles and vesicles. A pseudogene of this gene is located on chromosome 10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

DYNC1I2 links:

DYNC1I2 (HGNC:):

DYNC1I2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1I2. . Gene score misZ 2.4516 (greater than the threshold 3.09). Trascript score misZ 3.3484 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with microcephaly and structural brain anomalies.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1I2	NM_001378.3 linkuse as main transcript	c.523G>T	p.Asp175Tyr	missense_variant	8/18	ENST00000397119.8	NP_001369.1	Q13409-1A0A140VKE9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8 linkuse as main transcript	c.523G>T	p.Asp175Tyr	missense_variant	8/18	1	NM_001378.3	ENSP00000380308.3		Q13409-1

Frequencies

GnomAD3 genomes

AF:

0.0000140

AC:

AN:

142618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000160

AC:

AN:

1064872

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

537528

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000222

GnomAD4 genome

AF:

0.0000140

AC:

AN:

142618

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

68764

show subpopulations

Gnomad4 AFR

AF:

0.0000261

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.523G>T (p.D175Y) alteration is located in exon 8 (coding exon 7) of the DYNC1I2 gene. This alteration results from a G to T substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;D;.;T;.;.;T;.;D;.;T;.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;.;.;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.46

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.073

MutationAssessor

Uncertain

2.2

.;.;M;.;.;.;.;.;.;M;M;.;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.38

Sift

Benign

0.039

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;T;D;T;D;T;T;D;D;D;D;D;D;D;D

Polyphen

0.79, 0.26, 0.0020

.;P;B;.;.;P;P;.;B;B;.;.;.;.;.

Vest4

0.22, 0.19, 0.21, 0.22, 0.21, 0.21, 0.18, 0.20

MutPred

0.36

.;.;Gain of phosphorylation at D175 (P = 2e-04);.;.;.;.;.;.;Gain of phosphorylation at D175 (P = 2e-04);Gain of phosphorylation at D175 (P = 2e-04);.;.;.;.;

MVP

0.88

MPC

0.72

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.29

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over