chr16-8859224-C-G

Variant names:

• chr16-8859224-C-G
• rs8097
• NM_014316.4:c.105G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_014316.4(CARHSP1):​c.105G>C​(p.Arg35Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,597,628 control chromosomes in the GnomAD database, including 325,851 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (22972 hom., cov: 23)
  • Exomes 𝑓: 0.64 (302879 hom.)
• Consequence: CARHSP1 NM_014316.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 21 publications found

Genes affected

CARHSP1 (HGNC:17150): (calcium regulated heat stable protein 1) Enables mRNA 3'-UTR binding activity. Predicted to be involved in regulation of mRNA stability. Predicted to be located in P granule and cytosol. Predicted to be active in cytoplasm. Predicted to colocalize with cytoplasmic exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

PMM2 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen

LOC100130283 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8201111E-6).
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARHSP1	NM_014316.4	c.105G>C	p.Arg35Arg	synonymous_variant	Exon 2 of 4	ENST00000311052.10	NP_055131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARHSP1	ENST00000311052.10	c.105G>C	p.Arg35Arg	synonymous_variant	Exon 2 of 4	1	NM_014316.4	ENSP00000311847.4

Frequencies

GnomAD3 genomes AF: 0.560 AC: 78081 AN: 139552 Hom.: 22971 Cov.: 23

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.571

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.621 AC: 151805 AN: 244478 AF XY: 0.632

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.645

Gnomad EAS exome AF: 0.680

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.642 AC: 935909 AN: 1457958 Hom.: 302879 Cov.: 45 AF XY: 0.644 AC XY: 466947 AN XY: 725266

African (AFR) AF: 0.362 AC: 12097 AN: 33446

American (AMR) AF: 0.524 AC: 23304 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 16977 AN: 26060

East Asian (EAS) AF: 0.683 AC: 27052 AN: 39628

South Asian (SAS) AF: 0.693 AC: 59537 AN: 85970

European-Finnish (FIN) AF: 0.667 AC: 35076 AN: 52626

Middle Eastern (MID) AF: 0.642 AC: 3698 AN: 5762

European-Non Finnish (NFE) AF: 0.649 AC: 720192 AN: 1109720

Other (OTH) AF: 0.630 AC: 37976 AN: 60274

GnomAD4 genome AF: 0.559 AC: 78109 AN: 139670 Hom.: 22972 Cov.: 23 AF XY: 0.559 AC XY: 37259 AN XY: 66682

African (AFR) AF: 0.371 AC: 14082 AN: 37914

American (AMR) AF: 0.511 AC: 6676 AN: 13052

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2199 AN: 3370

East Asian (EAS) AF: 0.664 AC: 3186 AN: 4798

South Asian (SAS) AF: 0.696 AC: 2139 AN: 3072

European-Finnish (FIN) AF: 0.667 AC: 6244 AN: 9362

Middle Eastern (MID) AF: 0.563 AC: 162 AN: 288

European-Non Finnish (NFE) AF: 0.644 AC: 41968 AN: 65214

Other (OTH) AF: 0.566 AC: 973 AN: 1720

Alfa AF: 0.547 Hom.: 3172

Bravo AF: 0.543

TwinsUK AF: 0.650 AC: 2409

ALSPAC AF: 0.657 AC: 2531

ESP6500AA AF: 0.387 AC: 1699

ESP6500EA AF: 0.641 AC: 5509

ExAC AF: 0.618 AC: 74921

Asia WGS AF: 0.643 AC: 2237 AN: 3478

EpiCase AF: 0.648

EpiControl AF: 0.647

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.4
DANN	Benign	0.95
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0000028	T
PhyloP100		-0.16
PROVEAN	Pathogenic	-6.0	D
GERP RS		0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs8097; hg19: chr16-8953081; COSMIC: COSV60683525; COSMIC: COSV60683525;