rs73527702

chr7-158879714-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018051.5(DYNC2I1):c.604C>G(p.Leu202Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,594,884 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0092 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.542

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) and may facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030198991).
• BP6: Variant 7-158879714-C-G is Benign according to our data. Variant chr7-158879714-C-G is described in ClinVar as [Benign]. Clinvar id is 474631.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-158879714-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00919 (1396/151986) while in subpopulation AFR AF= 0.0307 (1272/41414). AF 95% confidence interval is 0.0293. There are 10 homozygotes in gnomad4. There are 661 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2I1	NM_018051.5	c.604C>G	p.Leu202Val	missense_variant	5/25	ENST00000407559.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.604C>G	p.Leu202Val	missense_variant	5/25	1	NM_018051.5	P1

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1396 AN: 151868 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00636

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00278 AC: 644 AN: 231538 Hom.: 7 AF XY: 0.00214 AC XY: 271 AN XY: 126800

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.000232

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00119 AC: 1724 AN: 1442898 Hom.: 17 Cov.: 30 AF XY: 0.00111 AC XY: 800 AN XY: 718656

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.000764

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000946

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00919 AC: 1396 AN: 151986 Hom.: 10 Cov.: 32 AF XY: 0.00890 AC XY: 661 AN XY: 74272

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00324 Hom.: 1

Bravo AF: 0.0109

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0261 AC: 102

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.00290 AC: 351

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short-rib thoracic dysplasia 8 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Benign	0.21	T
Sift4G	Benign	0.37	T
Polyphen		0.60	P
Vest4		0.081
MVP		0.33
MPC		0.40
ClinPred		0.0054	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.099

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: rs73527702; hg19: chr7-158672405;