21-17796838-G-T

Variant names:

• chr21-17796838-G-T
• rs1047978
• NM_001100420.2:c.408C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100420.2(C21orf91):​c.408C>A​(p.Asp136Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 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: not found (cov: 33)
• Consequence: C21orf91 NM_001100420.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.915
• Publications: 27 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38547498).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf91	NM_001100420.2	MANE Select	c.408C>A	p.Asp136Glu	missense	Exon 3 of 5	NP_001093890.1
	C21orf91	NM_017447.4		c.408C>A	p.Asp136Glu	missense	Exon 3 of 5	NP_059143.3
	C21orf91	NM_001100421.2		c.408C>A	p.Asp136Glu	missense	Exon 3 of 4	NP_001093891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf91	ENST00000284881.9	TSL:2 MANE Select	c.408C>A	p.Asp136Glu	missense	Exon 3 of 5	ENSP00000284881.4	Q9NYK6-1
	C21orf91	ENST00000400558.7	TSL:1	c.408C>A	p.Asp136Glu	missense	Exon 3 of 4	ENSP00000383403.3	Q9NYK6-2
	C21orf91	ENST00000908059.1		c.408C>A	p.Asp136Glu	missense	Exon 3 of 5	ENSP00000578118.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.92
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.053	T
Sift4G	Uncertain	0.020	D
Vest4		0.25
MutPred		0.34		Gain of disorder (P = 0.1272)
MVP		0.25
MPC		0.55
ClinPred		0.95	D
GERP RS		3.4
gMVP		0.35
Mutation Taster		=99/1	polymorphism

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: rs1047978; hg19: chr21-19169155;