rs1558660477

Variant names:

• chr2-43776899-G-A
• rs1558660477
• NM_016008.4:c.126G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-43776899-G-A
• chr2-43776899-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016008.4(DYNC2LI1):​c.126G>A​(p.Gly42Gly) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000786 in 1,272,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: DYNC2LI1 NM_016008.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	NP_057092.2
	DYNC2LI1	NM_001348913.2		c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 14	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.126G>A	p.Gly42Gly	splice_region synonymous	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.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	ENSP00000260605.8	Q8TCX1-1
	DYNC2LI1	ENST00000605786.5	TSL:1	c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	ENSP00000474032.1	Q8TCX1-2
	DYNC2LI1	ENST00000378587.3	TSL:1	c.75G>A	p.Gly25Gly	splice_region synonymous	Exon 1 of 11	ENSP00000367850.3	H7BYC8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.86e-7 AC: 1 AN: 1272534 Hom.: 0 Cov.: 18 AF XY: 0.00000156 AC XY: 1 AN XY: 641814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27714

American (AMR) AF: 0.00 AC: 0 AN: 39714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24486

East Asian (EAS) AF: 0.00 AC: 0 AN: 38382

South Asian (SAS) AF: 0.00 AC: 0 AN: 78014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 951818

Other (OTH) AF: 0.00 AC: 0 AN: 53902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		6.0
PromoterAI		-0.047	Neutral
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs1558660477; hg19: chr2-44004038;