rs61733022

Positions:

• chr7-158926425-A-G

Variant summary

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

The NM_018051.5(DYNC2I1):​c.2395A>G​(p.Ile799Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,613,352 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (149 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (133 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.723

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022461414).
• BP6: Variant 7-158926425-A-G is Benign according to our data. Variant chr7-158926425-A-G is described in ClinVar as [Benign]. Clinvar id is 474627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I1	NM_018051.5	c.2395A>G	p.Ile799Val	missense_variant	19/25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.2395A>G	p.Ile799Val	missense_variant	19/25	1	NM_018051.5	ENSP00000384290	P1
DYNC2I1	ENST00000444851.5	c.1553A>G	p.His518Arg	missense_variant, NMD_transcript_variant	14/20	1		ENSP00000392608
DYNC2I1	ENST00000467220.1	n.4194A>G		non_coding_transcript_exon_variant	14/20	2

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3674 AN: 152218 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00564 AC: 1399 AN: 247850 Hom.: 57 AF XY: 0.00430 AC XY: 578 AN XY: 134484

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00228 AC: 3325 AN: 1461016 Hom.: 133 Cov.: 35 AF XY: 0.00196 AC XY: 1423 AN XY: 726760

Gnomad4 AFR exome AF: 0.0837

Gnomad4 AMR exome AF: 0.00350

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.0242 AC: 3679 AN: 152336 Hom.: 149 Cov.: 33 AF XY: 0.0235 AC XY: 1751 AN XY: 74484

Gnomad4 AFR AF: 0.0842

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00412 Hom.: 27

Bravo AF: 0.0259

ESP6500AA AF: 0.0772 AC: 296

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00689 AC: 833

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.5
DANN	Benign	0.84
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Uncertain	0.026	D
Polyphen		0.10	B
Vest4		0.22
MVP		0.35
MPC		0.068
ClinPred		0.0038	T
GERP RS		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61733022; hg19: chr7-158719116;