rs72989738

Variant names:

• chr11-103166014-C-G
• rs72989738
• NM_001080463.2:c.4728C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-103166014-C-G
• chr11-103166014-C-T

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.4728C>G​(p.Asn1576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,532,380 control chromosomes in the GnomAD database, including 804 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N1576N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 32)
  • Exomes 𝑓: 0.030 (745 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.193
• Publications: 11 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

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

  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=0.0019398034).
• BP6: Variant 11-103166014-C-G is Benign according to our data. Variant chr11-103166014-C-G is described in ClinVar as Benign. ClinVar VariationId is 379420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0233 (3541/152226) while in subpopulation NFE AF = 0.0347 (2362/67994). AF 95% confidence interval is 0.0336. There are 59 homozygotes in GnomAd4. There are 1695 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.4728C>G	p.Asn1576Lys	missense	Exon 31 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.4728C>G	p.Asn1576Lys	missense	Exon 31 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.4728C>G	p.Asn1576Lys	missense	Exon 31 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.4728C>G	p.Asn1576Lys	missense	Exon 31 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+31595C>G		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3542 AN: 152108 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0212 AC: 3057 AN: 144372 AF XY: 0.0209

Gnomad AFR exome AF: 0.00527

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0301 AC: 41525 AN: 1380154 Hom.: 745 Cov.: 30 AF XY: 0.0293 AC XY: 19940 AN XY: 679476

African (AFR) AF: 0.00532 AC: 165 AN: 31006

American (AMR) AF: 0.0216 AC: 733 AN: 33890

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 1025 AN: 24830

East Asian (EAS) AF: 0.0000861 AC: 3 AN: 34828

South Asian (SAS) AF: 0.00531 AC: 395 AN: 74398

European-Finnish (FIN) AF: 0.0184 AC: 899 AN: 48840

Middle Eastern (MID) AF: 0.0480 AC: 252 AN: 5254

European-Non Finnish (NFE) AF: 0.0340 AC: 36365 AN: 1069856

Other (OTH) AF: 0.0295 AC: 1688 AN: 57252

GnomAD4 genome AF: 0.0233 AC: 3541 AN: 152226 Hom.: 59 Cov.: 32 AF XY: 0.0228 AC XY: 1695 AN XY: 74410

African (AFR) AF: 0.00544 AC: 226 AN: 41532

American (AMR) AF: 0.0302 AC: 462 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4828

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10606

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2362 AN: 67994

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0295 Hom.: 60

Bravo AF: 0.0243

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.00779 AC: 26

ESP6500EA AF: 0.0284 AC: 208

ExAC AF: 0.00976 AC: 561

Asia WGS AF: 0.00492 AC: 18 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	1	Jeune thoracic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.19
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.054
Sift	Benign	0.28	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.37		Gain of ubiquitination at N1576 (P = 0.0114)
MPC		0.070
ClinPred		0.0032	T
GERP RS		-2.1
Varity_R		0.070
gMVP		0.15
Mutation Taster		=87/13	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: rs72989738; hg19: chr11-103036743; COSMIC: COSV100519087;