rs886037860

Variant names:

• chr2-43800845-C-T
• rs886037860
• NM_016008.4:c.659C>T
• DYNC2LI1 p.Thr220Ile

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_016008.4(DYNC2LI1):​c.659C>T​(p.Thr220Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,577,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: DYNC2LI1 NM_016008.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.47
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-43800845-C-T is Pathogenic according to our data. Variant chr2-43800845-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253219.Status of the report is criteria_provided_single_submitter, 1 stars.

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.659C>T	p.Thr220Ile	missense	Exon 9 of 13	NP_057092.2
	DYNC2LI1	NM_001348913.2		c.662C>T	p.Thr221Ile	missense	Exon 9 of 14	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.659C>T	p.Thr220Ile	missense	Exon 9 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.659C>T	p.Thr220Ile	missense	Exon 9 of 13	ENSP00000260605.8	Q8TCX1-1
	DYNC2LI1	ENST00000605786.5	TSL:1	c.662C>T	p.Thr221Ile	missense	Exon 9 of 13	ENSP00000474032.1	Q8TCX1-2
	DYNC2LI1	ENST00000378587.3	TSL:1	c.608C>T	p.Thr203Ile	missense	Exon 8 of 11	ENSP00000367850.3	H7BYC8

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000168 AC: 4 AN: 237886 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000842 AC: 12 AN: 1425148 Hom.: 0 Cov.: 26 AF XY: 0.00000704 AC XY: 5 AN XY: 710068

African (AFR) AF: 0.00 AC: 0 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 41010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38786

South Asian (SAS) AF: 0.00 AC: 0 AN: 81470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1089196

Other (OTH) AF: 0.00 AC: 0 AN: 58844

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74214

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Short-rib thoracic dysplasia 15 with polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.079	T
Sift4G	Benign	0.37	T
Varity_R		0.23
gMVP		0.76
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037860; hg19: chr2-44027984;