rs73167274

Variant names:

• chr7-158934539-C-A
• rs73167274
• NM_018051.5:c.2768C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-158934539-C-A
• chr7-158934539-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018051.5(DYNC2I1):​c.2768C>A​(p.Pro923Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,551,660 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P923S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.17
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005575031).
• BP6: Variant 7-158934539-C-A is Benign according to our data. Variant chr7-158934539-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541526.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00262 (398/152188) while in subpopulation NFE AF = 0.0035 (238/67996). AF 95% confidence interval is 0.00314. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.2768C>A	p.Pro923Gln	missense	Exon 23 of 25	NP_060521.4
	DYNC2I1	NM_001350914.2		c.2630C>A	p.Pro877Gln	missense	Exon 23 of 25	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.2195C>A	p.Pro732Gln	missense	Exon 22 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.2768C>A	p.Pro923Gln	missense	Exon 23 of 25	ENSP00000384290.3	Q8WVS4
	DYNC2I1	ENST00000444851.5	TSL:1	n.*357C>A		non_coding_transcript_exon	Exon 18 of 20	ENSP00000392608.1	H7C022
	DYNC2I1	ENST00000444851.5	TSL:1	n.*357C>A		3_prime_UTR	Exon 18 of 20	ENSP00000392608.1	H7C022

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152072 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00690

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00251 AC: 399 AN: 158718 AF XY: 0.00220

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.000351

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00295 AC: 4126 AN: 1399472 Hom.: 13 Cov.: 32 AF XY: 0.00288 AC XY: 1985 AN XY: 690246

African (AFR) AF: 0.000443 AC: 14 AN: 31616

American (AMR) AF: 0.00314 AC: 111 AN: 35382

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25128

East Asian (EAS) AF: 0.00 AC: 0 AN: 35920

South Asian (SAS) AF: 0.0000889 AC: 7 AN: 78728

European-Finnish (FIN) AF: 0.00441 AC: 219 AN: 49648

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5690

European-Non Finnish (NFE) AF: 0.00333 AC: 3589 AN: 1079250

Other (OTH) AF: 0.00291 AC: 169 AN: 58110

GnomAD4 genome AF: 0.00262 AC: 398 AN: 152188 Hom.: 1 Cov.: 33 AF XY: 0.00276 AC XY: 205 AN XY: 74400

African (AFR) AF: 0.000963 AC: 40 AN: 41528

American (AMR) AF: 0.00236 AC: 36 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00690 AC: 73 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 67996

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00238

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00359 AC: 29

ExAC AF: 0.00124 AC: 125

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	DYNC2I1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	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	0.17
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.2
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.59
MPC		0.43
ClinPred		0.054	T
GERP RS		5.8
Varity_R		0.30
gMVP		0.35
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs73167274; hg19: chr7-158727230;