chr2-43776807-G-C

Variant names:

• chr2-43776807-G-C
• NM_016008.4:c.34G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016008.4(DYNC2LI1):​c.34G>C​(p.Ala12Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2LI1 NM_016008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2LI1	NM_016008.4	MANE Select	c.34G>C	p.Ala12Pro	missense	Exon 2 of 13	NP_057092.2
	DYNC2LI1	NM_001348913.2		c.34G>C	p.Ala12Pro	missense	Exon 2 of 14	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.34G>C	p.Ala12Pro	missense	Exon 2 of 14	NP_001335841.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2LI1	ENST00000260605.12	TSL:1 MANE Select	c.34G>C	p.Ala12Pro	missense	Exon 2 of 13	ENSP00000260605.8	Q8TCX1-1
	DYNC2LI1	ENST00000605786.5	TSL:1	c.34G>C	p.Ala12Pro	missense	Exon 2 of 13	ENSP00000474032.1	Q8TCX1-2
	DYNC2LI1	ENST00000406852.7	TSL:1	c.34G>C	p.Ala12Pro	missense	Exon 2 of 6	ENSP00000385738.3	Q8TCX1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.67
MutPred		0.41		Gain of disorder (P = 0.0382)
MVP		0.69
MPC		0.27
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		0.032	Neutral
Varity_R		0.48
gMVP		0.65
Mutation Taster		=49/51	disease causing

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

hg19: chr2-44003946;