rs2788478

Variant names:

• chr7-158879928-A-G
• rs2788478
• NM_018051.5:c.818A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-158879928-A-G
• chr7-158879928-A-T

Variant summary

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

The NM_018051.5(DYNC2I1):​c.818A>G​(p.Gln273Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,610,718 control chromosomes in the GnomAD database, including 136,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18990 hom., cov: 33)
  • Exomes 𝑓: 0.39 (117187 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.177
• Publications: 48 publications found

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]

DYNC2I1 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 8 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, ClinGen
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.2566614E-6).
• BP6: Variant 7-158879928-A-G is Benign according to our data. Variant chr7-158879928-A-G is described in ClinVar as Benign. ClinVar VariationId is 516219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018051.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	NM_018051.5	MANE Select	c.818A>G	p.Gln273Arg	missense	Exon 5 of 25	NP_060521.4
	DYNC2I1	NM_001350914.2		c.680A>G	p.Gln227Arg	missense	Exon 5 of 25	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.301A>G	p.Lys101Glu	missense	Exon 5 of 24	NP_001337844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.818A>G	p.Gln273Arg	missense	Exon 5 of 25	ENSP00000384290.3	Q8WVS4
	DYNC2I1	ENST00000444851.5	TSL:1	n.149A>G		non_coding_transcript_exon	Exon 1 of 20	ENSP00000392608.1	H7C022
	DYNC2I1	ENST00000860814.1		c.818A>G	p.Gln273Arg	missense	Exon 5 of 26	ENSP00000530873.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72760 AN: 151986 Hom.: 18949 Cov.: 33

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.439 AC: 107989 AN: 245938 AF XY: 0.438

Gnomad AFR exome AF: 0.687

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.392 AC: 571881 AN: 1458614 Hom.: 117187 Cov.: 53 AF XY: 0.395 AC XY: 286394 AN XY: 725872

African (AFR) AF: 0.689 AC: 22725 AN: 32980

American (AMR) AF: 0.428 AC: 18680 AN: 43662

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9056 AN: 26004

East Asian (EAS) AF: 0.700 AC: 27770 AN: 39680

South Asian (SAS) AF: 0.512 AC: 44005 AN: 86014

European-Finnish (FIN) AF: 0.378 AC: 20120 AN: 53282

Middle Eastern (MID) AF: 0.465 AC: 2670 AN: 5738

European-Non Finnish (NFE) AF: 0.362 AC: 402097 AN: 1111090

Other (OTH) AF: 0.412 AC: 24758 AN: 60164

GnomAD4 genome AF: 0.479 AC: 72857 AN: 152104 Hom.: 18990 Cov.: 33 AF XY: 0.485 AC XY: 36049 AN XY: 74362

African (AFR) AF: 0.679 AC: 28169 AN: 41476

American (AMR) AF: 0.457 AC: 6980 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3472

East Asian (EAS) AF: 0.722 AC: 3741 AN: 5180

South Asian (SAS) AF: 0.527 AC: 2542 AN: 4826

European-Finnish (FIN) AF: 0.374 AC: 3962 AN: 10586

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24817 AN: 67992

Other (OTH) AF: 0.456 AC: 963 AN: 2110

Alfa AF: 0.400 Hom.: 65581

Bravo AF: 0.490

TwinsUK AF: 0.373 AC: 1382

ALSPAC AF: 0.363 AC: 1399

ESP6500AA AF: 0.653 AC: 2463

ESP6500EA AF: 0.367 AC: 3004

ExAC AF: 0.441 AC: 53237

Asia WGS AF: 0.605 AC: 2101 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Short-rib thoracic dysplasia 8 with or without polydactyly (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.18
DANN	Benign	0.12
DEOGEN2	Benign	0.00067	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00049	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.013
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.085
ClinPred		0.00069	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.034
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: rs2788478; hg19: chr7-158672619; COSMIC: COSV68105764; COSMIC: COSV68105764;