16-70938692-T-C

Position:

• chr16-70938692-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001270974.2(HYDIN):​c.6917A>G​(p.Glu2306Gly) variant causes a missense change. The variant allele was found at a frequency of 0.693 in 1,612,490 control chromosomes in the GnomAD database, including 402,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (28289 hom., cov: 32)
  • Exomes 𝑓: 0.71 (374452 hom.)
• Consequence: HYDIN NM_001270974.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.29

Genes affected

HYDIN (HGNC:19368): (HYDIN axonemal central pair apparatus protein) This gene encodes a protein that may be involved in cilia motility. Mutations in this gene cause of autosomal recessive primary ciliary dyskinesia-5, a disorder characterized by the accumulation of cerebrospinal fluid within the ventricles of the brain. A duplicate copy of this gene has been found in humans on chromosome 1. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HYDIN. . Gene score misZ 0.81019 (greater than the threshold 3.09). Trascript score misZ 4.6175 (greater than threshold 3.09). GenCC has associacion of gene with primary ciliary dyskinesia 5, primary ciliary dyskinesia.
• BP4: Computational evidence support a benign effect (MetaRNN=3.3903714E-6).
• BP6: Variant 16-70938692-T-C is Benign according to our data. Variant chr16-70938692-T-C is described in ClinVar as [Benign]. Clinvar id is 402955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70938692-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYDIN	NM_001270974.2	c.6917A>G	p.Glu2306Gly	missense_variant	44/86	ENST00000393567.7	NP_001257903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYDIN	ENST00000393567.7	c.6917A>G	p.Glu2306Gly	missense_variant	44/86	5	NM_001270974.2	ENSP00000377197	P1
HYDIN	ENST00000309900.11	n.1437A>G		non_coding_transcript_exon_variant	9/20	1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86938 AN: 151788 Hom.: 28284 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.812

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.597

GnomAD3 exomes AF: 0.612 AC: 152378 AN: 249038 Hom.: 50394 AF XY: 0.624 AC XY: 84279 AN XY: 135158

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.444

Gnomad SAS exome AF: 0.506

Gnomad FIN exome AF: 0.756

Gnomad NFE exome AF: 0.750

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.705 AC: 1029903 AN: 1460584 Hom.: 374452 Cov.: 38 AF XY: 0.701 AC XY: 509502 AN XY: 726672

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.394

Gnomad4 ASJ exome AF: 0.665

Gnomad4 EAS exome AF: 0.432

Gnomad4 SAS exome AF: 0.510

Gnomad4 FIN exome AF: 0.759

Gnomad4 NFE exome AF: 0.757

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.573 AC: 86970 AN: 151906 Hom.: 28289 Cov.: 32 AF XY: 0.568 AC XY: 42182 AN XY: 74260

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.754

Gnomad4 NFE AF: 0.751

Gnomad4 OTH AF: 0.599

Alfa AF: 0.702 Hom.: 29993

Bravo AF: 0.542

ExAC AF: 0.614 AC: 74225

Asia WGS AF: 0.448 AC: 1556 AN: 3476

EpiCase AF: 0.737

EpiControl AF: 0.742

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2022	- -

Primary ciliary dyskinesia 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.0000034	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.058	P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Vest4		0.27
ClinPred		0.018	T
GERP RS		5.6
Varity_R		0.34
gMVP		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2502726; hg19: chr16-70972595; COSMIC: COSV59249510; COSMIC: COSV59249510;