rs116193143

Variant names:

• chr7-158911554-C-G
• rs116193143
• NM_018051.5:c.1465C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-158911554-C-G
• chr7-158911554-C-A
• chr7-158911554-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018051.5(DYNC2I1):​c.1465C>G​(p.Arg489Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,611,900 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.79
• Publications: 3 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), ClinGen, Laboratory for Molecular Medicine, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027967751).
• BP6: Variant 7-158911554-C-G is Benign according to our data. Variant chr7-158911554-C-G is described in ClinVar as Benign. ClinVar VariationId is 541527.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00258 (393/152194) while in subpopulation AFR AF = 0.009 (374/41536). AF 95% confidence interval is 0.00825. There are 2 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1465C>G	p.Arg489Gly	missense	Exon 12 of 25	NP_060521.4
	DYNC2I1	NM_001350914.2		c.1327C>G	p.Arg443Gly	missense	Exon 12 of 25	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.892C>G	p.Arg298Gly	missense	Exon 11 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.1465C>G	p.Arg489Gly	missense	Exon 12 of 25	ENSP00000384290.3	Q8WVS4
	DYNC2I1	ENST00000444851.5	TSL:1	n.796C>G		non_coding_transcript_exon	Exon 8 of 20	ENSP00000392608.1	H7C022
	DYNC2I1	ENST00000860814.1		c.1540C>G	p.Arg514Gly	missense	Exon 13 of 26	ENSP00000530873.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152076 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00905

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000793 AC: 196 AN: 247238 AF XY: 0.000619

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000308 AC: 449 AN: 1459706 Hom.: 0 Cov.: 30 AF XY: 0.000262 AC XY: 190 AN XY: 725988

African (AFR) AF: 0.0103 AC: 344 AN: 33386

American (AMR) AF: 0.000609 AC: 27 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111222

Other (OTH) AF: 0.000614 AC: 37 AN: 60292

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152194 Hom.: 2 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74412

African (AFR) AF: 0.00900 AC: 374 AN: 41536

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.00309

ESP6500AA AF: 0.00768 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000952 AC: 115

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Short-rib thoracic dysplasia 8 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.90
MPC		0.37
ClinPred		0.075	T
GERP RS		1.8
Varity_R		0.91
gMVP		0.72
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs116193143; hg19: chr7-158704245;