chr2-85754256-C-T

Variant names:

• chr2-85754256-C-T
• rs560944173
• NM_032827.7:c.67C>T

Variant summary

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

The NM_032827.7(ATOH8):​c.67C>T​(p.Leu23Phe) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.628
• Publications: 0 publications found

Genes affected

ATOH8 (HGNC:24126): (atonal bHLH transcription factor 8) Enables DNA-binding transcription factor activity and E-box binding activity. Involved in several processes, including SMAD protein signal transduction; positive regulation of endothelial cell differentiation; and regulation of gene expression. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.29233843).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032827.7. 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
	ATOH8	NM_032827.7	MANE Select	c.67C>T	p.Leu23Phe	missense	Exon 1 of 3	NP_116216.2	Q96SQ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATOH8	ENST00000306279.4	TSL:1 MANE Select	c.67C>T	p.Leu23Phe	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
	ATOH8	ENST00000716557.1		c.67C>T	p.Leu23Phe	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
	ATOH8	ENST00000881377.1		c.67C>T	p.Leu23Phe	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237432 AF XY: 0.00000763

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.55	N
PhyloP100		0.63
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Uncertain	0.019	D
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.26		Gain of methylation at K24 (P = 0.0372)
MVP		0.34
MPC		1.5
ClinPred		0.74	D
GERP RS		2.1
PromoterAI		-0.083	Neutral
Varity_R		0.20
gMVP		0.060
Mutation Taster		=95/5	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: rs560944173; hg19: chr2-85981379;