NM_016616.5:c.622T>C

Variant names:

• chr7-37867702-T-C
• rs10250905
• NM_016616.5:c.622T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016616.5(NME8):​c.622T>C​(p.Cys208Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,607,556 control chromosomes in the GnomAD database, including 441,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C208Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.77 (45537 hom., cov: 31)
  • Exomes 𝑓: 0.74 (396227 hom.)
• Consequence: NME8 NM_016616.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003852
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.17
• Publications: 37 publications found

Genes affected

NME8 (HGNC:16473): (NME/NM23 family member 8) This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function. Mutations in this gene are implicated in primary ciliary dyskinesia type 6.[provided by RefSeq, Nov 2009]

NME8 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia 6

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.56247E-6).
• BP6: Variant 7-37867702-T-C is Benign according to our data. Variant chr7-37867702-T-C is described in ClinVar as Benign. ClinVar VariationId is 164801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016616.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	NM_016616.5	MANE Select	c.622T>C	p.Cys208Arg	missense splice_region	Exon 11 of 18	NP_057700.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME8	ENST00000199447.9	TSL:1 MANE Select	c.622T>C	p.Cys208Arg	missense splice_region	Exon 11 of 18	ENSP00000199447.4
	NME8	ENST00000440017.5	TSL:1	c.622T>C	p.Cys208Arg	missense splice_region	Exon 10 of 16	ENSP00000397063.1
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-38+10357T>C		intron	N/A	ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117148 AN: 151884 Hom.: 45487 Cov.: 31

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.732 AC: 183376 AN: 250628 AF XY: 0.733

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.562

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.749

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.736 AC: 1071706 AN: 1455554 Hom.: 396227 Cov.: 32 AF XY: 0.737 AC XY: 533756 AN XY: 724446

African (AFR) AF: 0.877 AC: 29266 AN: 33370

American (AMR) AF: 0.679 AC: 30349 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 20450 AN: 26072

East Asian (EAS) AF: 0.565 AC: 22405 AN: 39626

South Asian (SAS) AF: 0.748 AC: 64446 AN: 86102

European-Finnish (FIN) AF: 0.729 AC: 38910 AN: 53374

Middle Eastern (MID) AF: 0.773 AC: 4438 AN: 5744

European-Non Finnish (NFE) AF: 0.738 AC: 816892 AN: 1106424

Other (OTH) AF: 0.740 AC: 44550 AN: 60172

GnomAD4 genome AF: 0.771 AC: 117255 AN: 152002 Hom.: 45537 Cov.: 31 AF XY: 0.768 AC XY: 57048 AN XY: 74308

African (AFR) AF: 0.872 AC: 36165 AN: 41466

American (AMR) AF: 0.726 AC: 11070 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2723 AN: 3468

East Asian (EAS) AF: 0.577 AC: 2968 AN: 5142

South Asian (SAS) AF: 0.737 AC: 3553 AN: 4820

European-Finnish (FIN) AF: 0.713 AC: 7533 AN: 10570

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50648 AN: 67972

Other (OTH) AF: 0.775 AC: 1633 AN: 2108

Alfa AF: 0.760 Hom.: 77604

Bravo AF: 0.775

TwinsUK AF: 0.741 AC: 2748

ALSPAC AF: 0.738 AC: 2844

ESP6500AA AF: 0.864 AC: 3805

ESP6500EA AF: 0.748 AC: 6432

ExAC AF: 0.737 AC: 89500

Asia WGS AF: 0.661 AC: 2300 AN: 3478

EpiCase AF: 0.748

EpiControl AF: 0.757

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 6 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:1

Dec 01, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.061	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.070
Sift	Benign	0.046	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0010	B
Vest4		0.13
MPC		0.026
ClinPred		0.010	T
GERP RS		4.9
Varity_R		0.32
gMVP		0.49
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.048
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: rs10250905; hg19: chr7-37907304; COSMIC: COSV52253781; COSMIC: COSV52253781;