21-17796901-G-C

Variant names:

• chr21-17796901-G-C
• rs2824495
• NM_001100420.2:c.345C>G

Variant summary

Our verdict is Benign. The variant received -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. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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]

ENSG00000244676 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100420.2. 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
	C21orf91	NM_001100420.2	MANE Select	c.345C>G	p.Asn115Lys	missense	Exon 3 of 5	NP_001093890.1
	C21orf91	NM_017447.4		c.345C>G	p.Asn115Lys	missense	Exon 3 of 5	NP_059143.3
	C21orf91	NM_001100421.2		c.345C>G	p.Asn115Lys	missense	Exon 3 of 4	NP_001093891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf91	ENST00000284881.9	TSL:2 MANE Select	c.345C>G	p.Asn115Lys	missense	Exon 3 of 5	ENSP00000284881.4
	C21orf91	ENST00000400558.7	TSL:1	c.345C>G	p.Asn115Lys	missense	Exon 3 of 4	ENSP00000383403.3
	C21orf91	ENST00000400559.7	TSL:5	c.345C>G	p.Asn115Lys	missense	Exon 3 of 5	ENSP00000383404.3

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

GnomAD2 exomes AF: 0.217 AC: 54042 AN: 249026 AF XY: 0.211

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 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

African (AFR) AF: 0.201 AC: 6731 AN: 33434

American (AMR) AF: 0.259 AC: 11591 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4052 AN: 26126

East Asian (EAS) AF: 0.388 AC: 15409 AN: 39684

South Asian (SAS) AF: 0.187 AC: 16169 AN: 86240

European-Finnish (FIN) AF: 0.138 AC: 7352 AN: 53300

Middle Eastern (MID) AF: 0.134 AC: 770 AN: 5766

European-Non Finnish (NFE) AF: 0.215 AC: 239186 AN: 1111070

Other (OTH) AF: 0.214 AC: 12896 AN: 60364

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

African (AFR) AF: 0.207 AC: 8598 AN: 41482

American (AMR) AF: 0.244 AC: 3732 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 536 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2063 AN: 5174

South Asian (SAS) AF: 0.193 AC: 931 AN: 4820

European-Finnish (FIN) AF: 0.127 AC: 1341 AN: 10582

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13854 AN: 67980

Other (OTH) AF: 0.170 AC: 359 AN: 2106

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 v4.9

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
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.77
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.035
Sift	Benign	0.66	T
Sift4G	Benign	0.32	T
Vest4		0.035
MutPred		0.23		Gain of ubiquitination at N115 (P = 0.006)
MPC		0.17
ClinPred		0.0025	T
GERP RS		0.94
gMVP		0.076
Mutation Taster		=97/3	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: rs2824495; hg19: chr21-19169218; COSMIC: COSV53032946; COSMIC: COSV53032946;