5-178153642-C-G

Variant names:

• chr5-178153642-C-G
• rs41285577
• NM_017838.4:c.160+16G>C

Variant summary

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

The NM_017838.4(NHP2):​c.160+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,613,782 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 33)
  • Exomes 𝑓: 0.014 (264 hom.)
• Consequence: NHP2 NM_017838.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.30
• Publications: 2 publications found

Genes affected

NHP2 (HGNC:14377): (NHP2 ribonucleoprotein) This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA3 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nhp2p. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]

NHP2 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-178153642-C-G is Benign according to our data. Variant chr5-178153642-C-G is described in ClinVar as Benign. ClinVar VariationId is 260941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017838.4. 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
	NHP2	NM_017838.4	MANE Select	c.160+16G>C		intron	N/A	NP_060308.1
	NHP2	NM_001396110.1		c.160+16G>C		intron	N/A	NP_001383039.1
	NHP2	NM_001034833.2		c.160+16G>C		intron	N/A	NP_001030005.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHP2	ENST00000274606.8	TSL:1 MANE Select	c.160+16G>C		intron	N/A	ENSP00000274606.4
	NHP2	ENST00000510363.1	TSL:1	n.227+16G>C		intron	N/A
	NHP2	ENST00000940843.1		c.160+16G>C		intron	N/A	ENSP00000610902.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2594 AN: 152232 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.0859

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.00705

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0172 AC: 4306 AN: 249626 AF XY: 0.0163

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00981

Gnomad ASJ exome AF: 0.00768

Gnomad EAS exome AF: 0.0922

Gnomad FIN exome AF: 0.00657

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0137 AC: 20036 AN: 1461432 Hom.: 264 Cov.: 31 AF XY: 0.0134 AC XY: 9742 AN XY: 727016

African (AFR) AF: 0.0223 AC: 748 AN: 33474

American (AMR) AF: 0.0112 AC: 501 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00767 AC: 200 AN: 26092

East Asian (EAS) AF: 0.0770 AC: 3057 AN: 39690

South Asian (SAS) AF: 0.00676 AC: 583 AN: 86218

European-Finnish (FIN) AF: 0.00699 AC: 373 AN: 53362

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5766

European-Non Finnish (NFE) AF: 0.0121 AC: 13416 AN: 1111774

Other (OTH) AF: 0.0168 AC: 1013 AN: 60366

GnomAD4 genome AF: 0.0170 AC: 2595 AN: 152350 Hom.: 42 Cov.: 33 AF XY: 0.0167 AC XY: 1248 AN XY: 74510

African (AFR) AF: 0.0213 AC: 884 AN: 41586

American (AMR) AF: 0.0166 AC: 254 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.0859 AC: 445 AN: 5180

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4832

European-Finnish (FIN) AF: 0.00705 AC: 75 AN: 10632

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 823 AN: 68032

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.00587 Hom.: 1

Bravo AF: 0.0198

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.37
PhyloP100		-1.3
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Mutation Taster		=100/0	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: rs41285577; hg19: chr5-177580643; COSMIC: COSV51070810; COSMIC: COSV51070810;