NM_016008.4:c.994-44A>G

Variant names:

• chr2-43809661-A-G
• rs4952683
• NM_016008.4:c.994-44A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016008.4(DYNC2LI1):​c.994-44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,439,108 control chromosomes in the GnomAD database, including 35,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5846 hom., cov: 32)
  • Exomes 𝑓: 0.21 (29586 hom.)
• Consequence: DYNC2LI1 NM_016008.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.375
• Publications: 4 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]

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG5 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• sitosterolemia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-43809661-A-G is Benign according to our data. Variant chr2-43809661-A-G is described in ClinVar as Benign. ClinVar VariationId is 1245873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2LI1	NM_016008.4	c.994-44A>G		intron_variant	Intron 12 of 12	ENST00000260605.12	NP_057092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2LI1	ENST00000260605.12	c.994-44A>G		intron_variant	Intron 12 of 12	1	NM_016008.4	ENSP00000260605.8
DYNC2LI1	ENST00000605786.5	c.997-44A>G		intron_variant	Intron 12 of 12	1		ENSP00000474032.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39318 AN: 152040 Hom.: 5834 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.240 AC: 53485 AN: 222710 AF XY: 0.233

Gnomad AFR exome AF: 0.412

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.171

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.207 AC: 266430 AN: 1286950 Hom.: 29586 Cov.: 18 AF XY: 0.207 AC XY: 134411 AN XY: 647920

African (AFR) AF: 0.409 AC: 11938 AN: 29174

American (AMR) AF: 0.364 AC: 14206 AN: 39056

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5076 AN: 24618

East Asian (EAS) AF: 0.155 AC: 5955 AN: 38478

South Asian (SAS) AF: 0.280 AC: 21802 AN: 77844

European-Finnish (FIN) AF: 0.162 AC: 8541 AN: 52724

Middle Eastern (MID) AF: 0.228 AC: 1165 AN: 5110

European-Non Finnish (NFE) AF: 0.193 AC: 186085 AN: 965432

Other (OTH) AF: 0.214 AC: 11662 AN: 54514

GnomAD4 genome AF: 0.259 AC: 39362 AN: 152158 Hom.: 5846 Cov.: 32 AF XY: 0.258 AC XY: 19187 AN XY: 74412

African (AFR) AF: 0.407 AC: 16867 AN: 41474

American (AMR) AF: 0.295 AC: 4510 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 706 AN: 3466

East Asian (EAS) AF: 0.162 AC: 838 AN: 5180

South Asian (SAS) AF: 0.279 AC: 1346 AN: 4826

European-Finnish (FIN) AF: 0.144 AC: 1524 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12874 AN: 67996

Other (OTH) AF: 0.234 AC: 495 AN: 2114

Alfa AF: 0.235 Hom.: 1080

Bravo AF: 0.277

Asia WGS AF: 0.223 AC: 775 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.66
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs4952683; hg19: chr2-44036800;