2-43776871-T-C

Position:

• chr2-43776871-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016008.4(DYNC2LI1):​c.98T>C​(p.Phe33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,594,682 control chromosomes in the GnomAD database, including 136,513 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (22438 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114075 hom.)
• Consequence: DYNC2LI1 NM_016008.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.595019E-7).
• BP6: Variant 2-43776871-T-C is Benign according to our data. Variant chr2-43776871-T-C is described in ClinVar as [Benign]. Clinvar id is 1255528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2LI1	NM_016008.4	c.98T>C	p.Phe33Ser	missense_variant	2/13	ENST00000260605.12	NP_057092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2LI1	ENST00000260605.12	c.98T>C	p.Phe33Ser	missense_variant	2/13	1	NM_016008.4	ENSP00000260605	P4

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76067 AN: 151950 Hom.: 22372 Cov.: 32

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.476

GnomAD3 exomes AF: 0.423 AC: 103053 AN: 243646 Hom.: 24286 AF XY: 0.418 AC XY: 55098 AN XY: 131732

Gnomad AFR exome AF: 0.836

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.179

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.385 AC: 555749 AN: 1442614 Hom.: 114075 Cov.: 27 AF XY: 0.388 AC XY: 278609 AN XY: 718068

Gnomad4 AFR exome AF: 0.846

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.415

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.347

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.501 AC: 76189 AN: 152068 Hom.: 22438 Cov.: 32 AF XY: 0.498 AC XY: 36980 AN XY: 74308

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.477

Alfa AF: 0.385 Hom.: 22270

Bravo AF: 0.524

TwinsUK AF: 0.363 AC: 1345

ALSPAC AF: 0.362 AC: 1397

ESP6500AA AF: 0.818 AC: 3602

ESP6500EA AF: 0.365 AC: 3138

ExAC AF: 0.436 AC: 52910

Asia WGS AF: 0.385 AC: 1343 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Short-rib thoracic dysplasia 15 with polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.015	T;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.24	T;T;T;T
MetaRNN	Benign	6.6e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.8	N;N;N;.
REVEL	Benign	0.27
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.12
MPC		0.056
ClinPred		0.011	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs2288709; hg19: chr2-44004010; COSMIC: COSV53184694; COSMIC: COSV53184694;