Genetic Variant DYNC1I2:p.Pro74Ser (chr2-171692888-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378.3(DYNC1I2):c.220C>T(p.Pro74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P74A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DYNC1I2
NM_001378.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.09

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly and structural brain anomalies
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

DYNC1I2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23531285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3 link	c.220C>T	p.Pro74Ser	missense_variant	Exon 3 of 18	ENST00000397119.8	NP_001369.1	Q13409-1A0A140VKE9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8 link	c.220C>T	p.Pro74Ser	missense_variant	Exon 3 of 18	1	NM_001378.3	ENSP00000380308.3		Q13409-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440062

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33008

American (AMR)

AF:

0.00

AC:

AN:

42020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25606

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.00

AC:

AN:

82708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099772

Other (OTH)

AF:

0.00

AC:

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.0082

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;.;T;.;T;.;.;T;.;T;.;.;T;T;T;.;.;.;T

Eigen

Benign

0.078

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.024

MetaRNN

Benign

0.24

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

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.47

.;N;N;N;.;N;N;.;N;N;.;N;.;.;.;.;.;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.3

N;N;N;N;D;N;N;D;N;N;D;N;N;D;D;D;D;D;D

REVEL

Benign

0.14

Sift

Benign

0.18

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

Sift4G

Benign

0.061

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

Polyphen

0.25, 0.096, 0.036

.;B;B;.;.;B;B;.;B;B;.;.;.;.;.;.;.;.;.

Vest4

0.19, 0.20, 0.20, 0.21, 0.19, 0.16, 0.21, 0.22

MutPred

0.21

Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);Gain of glycosylation at P74 (P = 0.0423);

MVP

0.81

MPC

0.52

ClinPred

0.51

GERP RS

5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.093

gMVP

0.15

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr2-171692888-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over