2-43794508-G-C

Variant names:

• chr2-43794508-G-C
• rs769975073
• NM_016008.4:c.372G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_016008.4(DYNC2LI1):​c.372G>C​(p.Trp124Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2LI1 NM_016008.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_016008.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2LI1	NM_016008.4	MANE Select	c.372G>C	p.Trp124Cys	missense	Exon 6 of 13	NP_057092.2
	DYNC2LI1	NM_001348913.2		c.372G>C	p.Trp124Cys	missense	Exon 6 of 14	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.372G>C	p.Trp124Cys	missense	Exon 6 of 14	NP_001335841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2LI1	ENST00000260605.12	TSL:1 MANE Select	c.372G>C	p.Trp124Cys	missense	Exon 6 of 13	ENSP00000260605.8
	DYNC2LI1	ENST00000605786.5	TSL:1	c.372G>C	p.Trp124Cys	missense	Exon 6 of 13	ENSP00000474032.1
	DYNC2LI1	ENST00000378587.3	TSL:1	c.321G>C	p.Trp107Cys	missense	Exon 5 of 11	ENSP00000367850.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.77		Loss of ubiquitination at K119 (P = 0.058)
MVP		0.56
MPC		0.32
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99
gMVP		0.92
Mutation Taster		=169/131	polymorphism

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

Other links and lift over

dbSNP: rs769975073; hg19: chr2-44021647; COSMIC: COSV53185726; COSMIC: COSV53185726;