4-154235446-G-T

Variant names:

• chr4-154235446-G-T
• rs149548848
• NM_001358235.2:c.9206C>A

Variant summary

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

The NM_001358235.2(DCHS2):​c.9206C>A​(p.Pro3069Gln) 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. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3069L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCHS2 NM_001358235.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 11 publications found

Genes affected

DCHS2 (HGNC:23111): (dachsous cadherin-related 2) This gene encodes a large protein that contains many cadherin domains and likely functions in cell adhesion. Genome-wide association studies suggest that this gene may be important in Alzheimer's disease, compressive strength index, and appendicular lean mass. [provided by RefSeq, May 2017]

ENSG00000280241 (HGNC:58900):

LOC101927947 (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=0.3119159).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358235.2. 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
	DCHS2	NM_001358235.2	MANE Select	c.9206C>A	p.Pro3069Gln	missense	Exon 20 of 20	NP_001345164.1	Q6V1P9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS2	ENST00000357232.10	TSL:1 MANE Select	c.9206C>A	p.Pro3069Gln	missense	Exon 20 of 20	ENSP00000349768.5	Q6V1P9-1
	DCHS2	ENST00000623607.4	TSL:1	n.7840C>A		non_coding_transcript_exon	Exon 25 of 25
	ENSG00000280241	ENST00000623325.1	TSL:5	n.98+28393G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.70	T
PhyloP100		3.1
PrimateAI	Benign	0.32	T
REVEL	Benign	0.16
MPC		0.40
ClinPred		0.84	D
GERP RS		5.8
gMVP		0.31
Mutation Taster		=65/35	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: rs149548848; hg19: chr4-155156598;