rs73527702

Variant names:

• chr7-158879714-C-G
• rs73527702
• NM_018051.5:c.604C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001350917.2(DYNC2I1):​c.-763C>G variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: DYNC2I1 NM_001350917.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.542
• Publications: 1 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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 -20 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 VariationId is 474631.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 = 0.00919 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350917.2. 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.604C>G	p.Leu202Val	missense	Exon 5 of 25	NP_060521.4
	DYNC2I1	NM_001350917.2		c.-763C>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 26	NP_001337846.1
	DYNC2I1	NM_001350918.2		c.-882C>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 27	NP_001337847.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.604C>G	p.Leu202Val	missense	Exon 5 of 25	ENSP00000384290.3
	DYNC2I1	ENST00000860814.1		c.604C>G	p.Leu202Val	missense	Exon 5 of 26	ENSP00000530873.1
	DYNC2I1	ENST00000961351.1		c.604C>G	p.Leu202Val	missense	Exon 5 of 26	ENSP00000631410.1

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

GnomAD2 exomes AF: 0.00278 AC: 644 AN: 231538 AF XY: 0.00214

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 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

African (AFR) AF: 0.0328 AC: 1034 AN: 31492

American (AMR) AF: 0.00465 AC: 174 AN: 37404

Ashkenazi Jewish (ASJ) AF: 0.000764 AC: 19 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000946 AC: 8 AN: 84578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00232 AC: 13 AN: 5598

European-Non Finnish (NFE) AF: 0.000279 AC: 309 AN: 1107074

Other (OTH) AF: 0.00282 AC: 167 AN: 59190

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

African (AFR) AF: 0.0307 AC: 1272 AN: 41414

American (AMR) AF: 0.00635 AC: 97 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67990

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.54
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
Mutation Taster		=92/8	polymorphism

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: rs73527702; hg19: chr7-158672405;