Genetic Variant NM_016008.4:c.98T>A (chr2-43776871-T-A) – 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_016008.4(DYNC2LI1):c.98T>A(p.Phe33Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. F33S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DYNC2LI1
NM_016008.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

0 publications found

Variant links:

Genes affected

DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

DYNC2LI1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 15 with polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2LI1 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=0.08823103).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016008.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2LI1	NM_016008.4	MANE Select	c.98T>A	p.Phe33Tyr	missense	Exon 2 of 13	NP_057092.2
DYNC2LI1	NM_001348913.2		c.98T>A	p.Phe33Tyr	missense	Exon 2 of 14	NP_001335842.1
DYNC2LI1	NM_001348912.2		c.98T>A	p.Phe33Tyr	missense	Exon 2 of 14	NP_001335841.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYNC2LI1	ENST00000260605.12	TSL:1 MANE Select	c.98T>A	p.Phe33Tyr	missense	Exon 2 of 13	ENSP00000260605.8	Q8TCX1-1
DYNC2LI1	ENST00000605786.5	TSL:1	c.98T>A	p.Phe33Tyr	missense	Exon 2 of 13	ENSP00000474032.1	Q8TCX1-2
DYNC2LI1	ENST00000378587.3	TSL:1	c.47T>A	p.Phe16Tyr	missense	Exon 1 of 11	ENSP00000367850.3	H7BYC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446830

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32760

American (AMR)

AF:

0.00

AC:

AN:

43034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103274

Other (OTH)

AF:

0.00

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.017

Eigen

Benign

-0.039

Eigen_PC

Benign

0.088

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.54

M_CAP

Benign

0.019

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

PhyloP100

3.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.11

REVEL

Benign

0.091

Sift

Benign

0.057

Sift4G

Benign

0.23

Polyphen

0.010

Vest4

0.20

MutPred

0.41

Loss of methylation at K32 (P = 0.0318)

MVP

0.15

MPC

0.043

ClinPred

0.74

GERP RS

5.4

PromoterAI

-0.0019

Neutral

(source)

Varity_R

0.22

gMVP

0.45

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over