rs144444098

chr7-158906001-C-Achr7-158906001-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_018051.5(DYNC2I1):c.1370C>A(p.Ser457Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000322 in 1,613,598 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.04

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068127513).
• BP6: Variant 7-158906001-C-A is Benign according to our data. Variant chr7-158906001-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 541524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (253/152276) while in subpopulation AFR AF= 0.00551 (229/41546). AF 95% confidence interval is 0.00493. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2I1	NM_018051.5	c.1370C>A	p.Ser457Tyr	missense_variant	11/25	ENST00000407559.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.1370C>A	p.Ser457Tyr	missense_variant	11/25	1	NM_018051.5	P1
DYNC2I1	ENST00000444851.5	c.701C>A	p.Ser234Tyr	missense_variant, NMD_transcript_variant	7/20	1
DYNC2I1	ENST00000467220.1	n.3169C>A		non_coding_transcript_exon_variant	6/20	2

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000446 AC: 111 AN: 248852 Hom.: 1 AF XY: 0.000348 AC XY: 47 AN XY: 135026

Gnomad AFR exome AF: 0.00595

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461322 Hom.: 1 Cov.: 30 AF XY: 0.000182 AC XY: 132 AN XY: 726942

Gnomad4 AFR exome AF: 0.00600

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74460

Gnomad4 AFR AF: 0.00551

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.00198

ESP6500AA AF: 0.00605 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000455 AC: 55

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYNC2I1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.60
MPC		0.42
ClinPred		0.055	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.21

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: rs144444098; hg19: chr7-158698692;