2-43776787-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_016008.4(DYNC2LI1):c.14C>G(p.Thr5Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000448 in 1,563,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: DYNC2LI1 NM_016008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023004979).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000461 (65/1411042) while in subpopulation AMR AF= 0.00137 (55/40168). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2LI1	NM_016008.4	c.14C>G	p.Thr5Ser	missense_variant	2/13	ENST00000260605.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2LI1	ENST00000260605.12	c.14C>G	p.Thr5Ser	missense_variant	2/13	1	NM_016008.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152020 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000219 AC: 50 AN: 228512 Hom.: 0 AF XY: 0.000145 AC XY: 18 AN XY: 124150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000943

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.0000461 AC: 65 AN: 1411042 Hom.: 0 Cov.: 26 AF XY: 0.0000370 AC XY: 26 AN XY: 702484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00137

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: 0.00000647

Gnomad4 OTH exome AF: 0.0000516

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152020 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74220

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000181

ExAC AF: 0.000231 AC: 28

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

Invitae

Aug 22, 2022

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 5 of the DYNC2LI1 protein (p.Thr5Ser). This variant is present in population databases (rs750299666, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DYNC2LI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1446256). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.76	N;N;N;.
REVEL	Benign	0.077
Sift	Benign	0.39	T;T;T;.
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.73	P;P;P;P
Vest4		0.44
MutPred		0.24		Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);
MVP		0.63
MPC		0.053
ClinPred		0.059	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.17
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750299666; hg19: chr2-44003926;