chr2-43776844-G-A

Position:

• chr2-43776844-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000260605.12(DYNC2LI1):​c.71G>A​(p.Gly24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,604,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DYNC2LI1 ENST00000260605.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.993

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02350223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2LI1	NM_016008.4	c.71G>A	p.Gly24Asp	missense_variant	2/13	ENST00000260605.12	NP_057092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2LI1	ENST00000260605.12	c.71G>A	p.Gly24Asp	missense_variant	2/13	1	NM_016008.4	ENSP00000260605	P4

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000613 AC: 15 AN: 244582 Hom.: 0 AF XY: 0.0000604 AC XY: 8 AN XY: 132474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1451912 Hom.: 0 Cov.: 29 AF XY: 0.0000291 AC XY: 21 AN XY: 722368

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.0000924

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: 0.0000235

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 24 of the DYNC2LI1 protein (p.Gly24Asp). This variant is present in population databases (rs146438889, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DYNC2LI1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T;.;.;.
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N;N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.41	N;N;N;.
REVEL	Benign	0.075
Sift	Benign	0.32	T;T;T;.
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.11
MVP		0.23
MPC		0.048
ClinPred		0.036	T
GERP RS		4.5
Varity_R		0.053
gMVP		0.31

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: rs146438889; hg19: chr2-44003983;