rs2824495

Positions:

• chr21-17796901-G-C
• chr21-17796901-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001100420.2(C21orf91):​c.345C>G​(p.Asn115Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,612,780 control chromosomes in the GnomAD database, including 38,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3487 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35089 hom.)
• Consequence: C21orf91 NM_001100420.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.770

Genes affected

C21orf91 (HGNC:16459): (chromosome 21 open reading frame 91) Predicted to be involved in cerebral cortex neuron differentiation and positive regulation of dendritic spine development. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021314323).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C21orf91	NM_001100420.2	c.345C>G	p.Asn115Lys	missense_variant	3/5	ENST00000284881.9
LOC124900465	XR_007067823.1	n.1605+40112G>C		intron_variant, non_coding_transcript_variant
C21orf91	NM_017447.4	c.345C>G	p.Asn115Lys	missense_variant	3/5
C21orf91	NM_001100421.2	c.345C>G	p.Asn115Lys	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C21orf91	ENST00000284881.9	c.345C>G	p.Asn115Lys	missense_variant	3/5	2	NM_001100420.2	P4
	ENST00000428689.5	n.71+3343G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31618 AN: 151978 Hom.: 3483 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.217 AC: 54042 AN: 249026 Hom.: 6466 AF XY: 0.211 AC XY: 28559 AN XY: 135134

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.215 AC: 314156 AN: 1460684 Hom.: 35089 Cov.: 33 AF XY: 0.213 AC XY: 154523 AN XY: 726766

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.208 AC: 31630 AN: 152096 Hom.: 3487 Cov.: 32 AF XY: 0.206 AC XY: 15327 AN XY: 74372

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.170

Alfa AF: 0.164 Hom.: 745

Bravo AF: 0.219

TwinsUK AF: 0.220 AC: 816

ALSPAC AF: 0.219 AC: 845

ESP6500AA AF: 0.214 AC: 777

ESP6500EA AF: 0.202 AC: 1655

ExAC AF: 0.217 AC: 26168

Asia WGS AF: 0.275 AC: 955 AN: 3476

EpiCase AF: 0.196

EpiControl AF: 0.207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.6
DANN	Benign	0.77
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.86	D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.32	T;T;T;.
Vest4		0.035
MutPred		0.23		Gain of ubiquitination at N115 (P = 0.006);Gain of ubiquitination at N115 (P = 0.006);Gain of ubiquitination at N115 (P = 0.006);Gain of ubiquitination at N115 (P = 0.006);
MPC		0.17
ClinPred		0.0025	T
GERP RS		0.94
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs2824495; hg19: chr21-19169218; COSMIC: COSV53032946; COSMIC: COSV53032946;