chr5-74635164-C-T

Position:

• chr5-74635164-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003633.4(ENC1):​c.1322G>A​(p.Ser441Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENC1 NM_003633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

ENC1 (HGNC:3345): (ectodermal-neural cortex 1) This gene encodes a member of the kelch-related family of actin-binding proteins. The encoded protein plays a role in the oxidative stress response as a regulator of the transcription factor Nrf2, and expression of this gene may play a role in malignant transformation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

ENC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENC1	NM_003633.4	c.1322G>A	p.Ser441Asn	missense_variant	2/3	ENST00000302351.9	NP_003624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENC1	ENST00000302351.9	c.1322G>A	p.Ser441Asn	missense_variant	2/3	1	NM_003633.4	ENSP00000306356.4
ENC1	ENST00000618628.4	c.1322G>A	p.Ser441Asn	missense_variant	3/4	5		ENSP00000479101.1
ENC1	ENST00000651128.1	c.1322G>A	p.Ser441Asn	missense_variant	3/4			ENSP00000499185.1
ENC1	ENST00000510316.5	c.1103G>A	p.Ser368Asn	missense_variant	2/3	2		ENSP00000423804.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.1322G>A (p.S441N) alteration is located in exon 2 (coding exon 1) of the ENC1 gene. This alteration results from a G to A substitution at nucleotide position 1322, causing the serine (S) at amino acid position 441 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;.
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.2	M;M;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Uncertain	0.045	D;D;T;D
Polyphen		0.027	B;B;.;B
Vest4		0.70
MutPred		0.48		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);
MVP		0.62
MPC		0.84
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73930989;